Sporadic Pancreatic Neuroendocrine Tumors Research Articles

Well-differentiated G1 and G2 pancreatic neuroendocrine tumors: a meta-analysis of published expanded DNA sequencing data.

Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in MEN1 as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs. A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020.A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25th of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package. Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was MEN1, with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in MEN1, VHL, CHEK2, BRCA2, PTEN, CDKN1B, and/or MUTYH) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The MEN1 point mutations/indels were distributed throughout MEN1. Overall, DAXX (16%, 37/225) and ATRX-variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. DAXX mutations occurred more frequently in PNETs with MEN1 mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways. The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).

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.

Improving fine needle aspiration to predict the tumor biological aggressiveness in pancreatic neuroendocrine tumors using Ki-67 proliferation index, phosphorylated histone H3 (PHH3), and BCL-2

IntroductionSurgery is the only known cure for sporadic pancreatic neuroendocrine tumors (PNETs). Therefore, the prediction of the PNETs biological aggressiveness evaluated on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has a significant impact on clinical management. The proliferation rate of Ki-67 in PNETs can help to predict the biological aggressiveness of the tumor. In addition, there is a relatively new proliferation marker called phosphorylated histone H3 (PHH3) that can identify and quantify dividing cells in tissue samples, which is a marker highly specific to mitotic figures. Other markers such as BCL-2 also contribute to tumorigenesis and may be involved in the differentiation of neuroendocrine cells. Materials and methodsA retrospective observational study was performed on patients undergoing surveillance for PNETs from January 2010 to May 2021. Data collection included the patients' age, sex, tumor location, tumor size in the surgical specimen, and tumor grade in FNA. The 2019 World Health Organization (WHO) classification guideline was followed to diagnose PNETs, including grade and stage. Immunohistochemical stainings for Ki-67, PHH3 and BCL-2 in PNETs were performed. ResultsAfter excluding cell blocks containing fewer than 100 tumor cells, 44 patients with EUS-FNA and surgical resection specimens were included in this study. There were 19 cases of G1 PNETs, 20 cases of G2 PNETs, and 5 cases of G3 PNETs. The grade assigned based on the Ki-67 index was higher and more sensitive than that based on the mitotic count using H&E slides in some cases of G2 and G3 PNETs. However, there was no significant difference between the mitotic count using PHH3-positive tumor cells and the Ki-67 index to grade PNETs.All grade 1 tumors (19 cases) on surgical resection specimens were correctly graded on FNA (100 % concordance rate). Within the 20 G2 PNETs, 15 cases of grade 2 on surgical resection specimens were graded correctly on FNA based on the Ki-67 index only. Five cases of grade 2 PNETs on surgical resection specimens were graded as grade 1 on FNA when using only the Ki-67 index. Three of five grade 3 tumors on surgical resection specimens were graded as grade 2 on FNA based on the Ki-67 index only. Using only FNA Ki-67 to predict PNET tumor grade, the concordance (accuracy) rate was 81.8 % in total. However, all these eight cases (5 cases of G2 PNETs and 3 cases of G3 PNETs) were graded correctly by using the Ki-67 index plus mitotic rate (using PHH3 IHC stains).Four of 18 (22.2 %) patients with PNETs were positive for BCL-2 stain. In these 4 cases positive for BCL-2 stains, 3 cases were G2 PNETs and one case was G3 PNETs. ConclusionGrade and the proliferative rate in EUS-FNA can be used to predict the tumor grade in surgical resection specimens. However, when using only FNA Ki-67 to predict PNET tumor grade, about 18 % of cases were downgraded by one level. To solve the problem, immunohistochemical staining for BCL-2 and especially PHH3 would be helpful. Our results demonstrated that the mitotic count using PHH3 IHC stains not only improved the accuracy and precision of PNET grading in the surgical resection specimens, but also could reliably be used in routine scoring of mitotic figures of FNA specimens.

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.

The role of DNA methylation in human pancreatic neuroendocrine tumours.

Pancreatic neuroendocrine tumours (PNETs) are the second most common pancreatic tumour. However, relatively little is known about their tumourigenic drivers, other than mutations involving the multiple endocrine neoplasia 1 (MEN1), ATRX chromatin remodeler, and death domain-associated protein genes, which are found in ~40% of sporadic PNETs. PNETs have a low mutational burden, thereby suggesting that other factors likely contribute to their development, including epigenetic regulators. One such epigenetic process, DNA methylation, silences gene transcription via 5'methylcytosine (5mC), and this is usually facilitated by DNA methyltransferase enzymes at CpG-rich areas around gene promoters. However, 5'hydroxymethylcytosine, which is the first epigenetic mark during cytosine demethylation, and opposes the function of 5mC, is associated with gene transcription, although the significance of this remains unknown, as it is indistinguishable from 5mC when conventional bisulfite conversion techniques are solely used. Advances in array-based technologies have facilitated the investigation of PNET methylomes and enabled PNETs to be clustered by methylome signatures, which has assisted in prognosis and discovery of new aberrantly regulated genes contributing to tumourigenesis. This review will discuss the biology of DNA methylation, its role in PNET development, and impact on prognostication and discovery of epigenome-targeted therapies.

Non-Interventional Management of Advanced Pancreatic Neuroendocrine Neoplasms in Patients with von Hippel-Lindau Disease.

Von Hippel-Lindau (VHL) is a rare autosomal dominant hereditary cancer predisposition syndrome. Patients with VHL have a high risk for developing retinal and central nervous system hemangioblastoma, pheochromocytoma, renal cell carcinoma, and pancreatic neuroendocrine neoplasms (PNEN). About a fifth of patients with VHL will develop PNEN, and only a tenth of them will develop metastatic or unresectable (advanced) PNEN requiring medical intervention. In this review, we performed a literature search for studies, written in English, on the medical interventions for VHL-related localized and advanced PNENs and their clinical outcomes. We detail the various medical interventions for this rare group of patients, including their mode of action and potential efficacy and toxicity. Finally, based on the current literature, we delineate a possible management algorithm for patients with VHL and advanced PNEN. We can conclude that data on the efficacy of various vascular endothelial growth factor (VEGF) receptor inhibitors, and on the efficacy of belzutifan, a novel hypoxia-inducible factor 2 inhibitor, for the management of advanced PNEN in VHL, are scarce. Hence, deduction from the management of sporadic PNEN is required, and is implemented in the proposed management algorithm provided within this review.

Clinical Prediction Models for Recurrence in Patients with Resectable Grade 1 and 2 Sporadic Non-Functional Pancreatic Neuroendocrine Tumors: A Systematic Review.

Recurrence after resection in patients with non-functional pancreatic neuroendocrine tumors (NF-pNET) has a considerable impact on overall survival. Accurate risk stratification will tailor optimal follow-up strategies. This systematic review assessed available prediction models, including their quality. This systematic review followed PRISMA and CHARMS guidelines. PubMed, Embase, and the Cochrane Library were searched up to December 2022 for studies that developed, updated, or validated prediction models for recurrence in resectable grade 1 or 2 NF-pNET. Studies were critically appraised. After screening 1883 studies, 14 studies with 3583 patients were included: 13 original prediction models and 1 prediction model validation. Four models were developed for preoperative and nine for postoperative use. Six models were presented as scoring systems, five as nomograms, and two as staging systems. The c statistic ranged from 0.67 to 0.94. The most frequently included predictors were tumor grade, tumor size, and lymph node positivity. Critical appraisal deemed all development studies as having a high risk of bias and the validation study as having a low risk of bias. This systematic review identified 13 prediction models for recurrence in resectable NF-pNET with external validations for 3 of them. External validation of prediction models improves their reliability and stimulates use in daily practice.

ODP300 c-MET expression in MEN1-associated neuroendocrine tumors

Abstract Multiple studies have shown that approximately 50-70% of patients with MEN1 die of causes directly related to MEN1 particularly gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). While non-functional GEP-NETs are the most common in the general population, gastrinomas (40%) are the most common functional GEP-NETs in patients with MEN1. c-MET is a proto-oncogene that encodes for c-MET, a tyrosine kinase receptor which promotes tumor cell motility, proliferation, survival, invasion, and metastasis. Studies in patients with sporadic gastrinomas and pancreatic NETs (PNETs) have shown that c-MET expression correlates with decreased survival. While c-MET inhibitors are currently in various stages of investigation for treatment of carcinoids and sporadic PNETs, data regarding their efficacy in patients with MEN1-related GEP NETs is lacking. The majority of trials in patients with GEP-NETs exclude or do not report the number of patients with MEN1. Importantly, somatic MEN1 mutations are observed in 20-40% of sporadic NETs (gastrinomas, PNETs, lung NETs, etc.) but correlation of cMET expression with the presence of somatic or germline MEN1 mutations has not been reported. We sought to investigate the expression of c-MET in tumor tissue from germline MEN1 patients with metastatic GEP-NETs. Methods We identified subjects with a germline positive MEN1 mutation and pathologically confirmed distant metastasis who had a follow-up visit between 2018-2020. Of these, we selected subjects with available tissue specimens (including either multiple organ sources or different tumor types). Where available, we identified specimens from multiple source or tumor types. Immunohistochemistry (IHC) to detect c-MET was performed with anti-MET (Cell Signaling) using the DAKO IHC kit (Agilent). IHC slides were imaged and observed to score the level of c-MET staining (-, 1+ to 5+). A score of 3+ or higher was considered consistent with overexpression. We investigated if age at initial GEP-NET presentation, tumor type, tissue source, tumor grade, total number of surgeries for GEP-NET, number of sites of distant metastasis and disease status from overall GEP-NET burden over the preceding 12 months (stable/progressive) predicted c-MET expression. Results Eight subjects with available tissue specimens were identified, of which six had tissue from multiple organs while five had tissue from multiple tumor types. Six subjects (75%) showed increased expression of c-MET in one or more tumor specimen(s). The frequency of c-MET overexpression varied with tumor types – carcinoids (n=2/2; 100%), gastrinomas (n=3/5; 60%) and non-functional tumors (n=3/6; 50%). c-MET expression also varied among different tumors in the same patient. Tumor tissue from liver (n=2/2), duodenum (n=3/4), stomach (n=1/1), ovary (n=1/1), pancreas (n= 1/5), and lymph nodes (n=1/3), all showed over-expression of c-MET. No clear predictors of c-MET overexpression emerged. Conclusion Our finding suggests a role for c-MET expression in personalizing therapy for patients with MEN1-related NETs with distant metastases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m.

LBODP106 Multi-omics Analyses Of MEN1 Missense Mutations Identify Disruption Of Menin-MLL And Menin-JunD Interactions As Critical Requirements For Molecular Pathogenicity

Abstract Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 endocrine tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes. Interestingly, we identified three missense mutations, R52G, E255K and E359K, which predominantly reduce the interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions. Presentation: No date and time listed

RF19 | PSUN349 Histone Eraser and Reader Targeting Epigenetic Inhibitors Are Effective in Pancreatic Neuroendocrine Tumours

Abstract Background The 5-year survival for metastatic pancreatic neuroendocrine tumours (PNETs) is &amp;lt;50%, and current therapies are not effective. Thus, there is an unmet clinical need for new therapies for patients with PNETs. PNETs frequently have mutations in chromatin remodelling genes, including in Multiple Endocrine Neoplasia type 1 (MEN1), encoding menin, which is mutated in up to 40% of sporadic PNETs, and is part of multiple histone modifying complexes including the SET1/MLL methyltransferases. Aim To examine multiple classes of epigenetic inhibitors and determine which may be effective in treating PNETs. Methods BON1 and QGP1 PNET cell lines, the bronchial NET cell line H727, and the non-NET cell line HEK293T were utilised to assess &amp;gt;150 small molecule inhibitors targeting: histone deacetylases (HDACs); histone acetyltransferases; histone demethylases (KDMs); histone methyltransferases; bromodomain-containing proteins; menin; and DNA methyltransferases (DNMTs). MTOR inhibitors, already used clinically for PNET patients, as well as drugs targeting other tumorigenic pathways e.g. the proto-oncogene SRC, were used as comparators. Efficacy of compounds was evaluated using the Cell Titer Blue cell viability assay, and the Caspase Glo 3/7 apoptosis assay. Results At a dose of 1mM for 7 days, 26 compounds (including HDAC, KDM, bromodomain and mTOR inhibitors) significantly decreased the viability of both the BON1 and QGP1 cell lines by &amp;gt;50%, compared to DMSO control treated cells. Upon increasing the dose to 10mM for 7 days, 34 additional compounds, making a total of 60 compounds (including inhibitors of menin and DNMTs), decreased viability of both BON1 and QGP1 cells by &amp;gt;50%; and 56 and 46 compounds also reduced viability of H727 and HEK293 cells by &amp;gt;50%, respectively. Apoptosis assays utilising the 60 above compounds, at 10mM for 7 days, revealed that 25, 18, 14, and 9 of them could increase apoptosis by &amp;gt;4-fold of BON1, QGP1, H727 and HEK293 cells, respectively. Ten compounds (2 KDM, 5 HDAC and 3 bromodomain inhibitors) that were effective in reducing viability by &amp;gt;50% as well as increasing apoptosis by &amp;gt;4-fold of NET cells, were selected for further dosing (0.1-10mM) and time course investigations (3-7 days). All 10 compounds significantly reduced viability of BON1 and QGP1 cells (p&amp;lt;0.01) after 3 days of treatment. The KDM and HDAC inhibitors showed the greatest efficacy, by significantly (p&amp;lt;0.05) reducing BON1 and QGP1 cell viability at as low as 25nM treatment for 3 days. The efficacy of bromodomain inhibitors was not attained until 1000nM treatment, however these inhibitors had very little effect on the non-NET HEK293 cells. Conclusions Compounds targeting HDACs, KDMs or bromodomain-containing proteins are effective in reducing viability by &amp;gt;50% and increasing apoptosis by &amp;gt;4-fold of NET cells, and thus provide novel agents for studying anti-cancer mechanisms and potential therapeutic options for PNETs. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.

Multi-omics analyses of MEN1 missense mutations identify disruption of menin–MLL and menin–JunD interactions as critical requirements for molecular pathogenicity

BackgroundLoss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors.ResultsHere, we applied and in silico screening approach for 253 disease-related MEN1 missense mutations in order to select a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/MLL2 and JunD complexes. Interestingly, we identified three missense mutations, R52G, E255K and E359K, which predominantly reduce the MLL1 and MLL2 interactions when compared with JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites.ConclusionsOur results underline the effects of MEN1 gene mutations in both familial and sporadic tumors of endocrine origin on the interactions of menin with the MLL1 and MLL2 histone H3K4 methyltransferase complexes and with JunD-containing transcription factors. Menin binding pocket mutants R52G, E255K and E359K have differential effects on MLL1/MLL2 and JunD interactions, which translate into differential genomic binding patterns. Our findings encourage future studies addressing the pathophysiological relevance of the separate MLL1/MLL2- and JunD-dependent functions of menin mutants in MEN1 disease model systems.

A Single-center Prospective Observational Study Investigating the Accuracy of Preoperative Diagnostic Procedures in the Assessment of Lymph Node Metastases in Nonfunctioning Pancreatic Neuroendocrine Tumors.

To determine the accuracy of preoperative imaging, including contrast-enhanced computed tomography (CE-CT), endoscopic ultrasound (EUS), and 68 Gallium-DOTATOC positron emission tomography ( 68 Ga-DOTATOC PET), in identifying nodal metastases (N+) in sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). An accurate preoperative identification of N+ in NF-PanNETs is critical for surgical planning. The accuracy of different imaging techniques in detecting lymph node (LN) metastases in NF-PanNETs has been poorly investigated. All consecutive patients undergoing surgery for sporadic NF-PanNETs (2018-2021) were enrolled in a prospective study (DETECTYON; NCT03918759). The accuracy of preoperative imaging techniques in detecting N+ was assessed through sensitivity, specificity positive and negative predictive values. Overall, 100 patients with NF-PanNETs underwent CE-CT, EUS, and 68 Ga-DOTATOC PET before pancreatic resection. LN metastases were found in 42 cases (42%). Sensitivity, specificity, positive predictive value, and negative predictive value of different imaging techniques were 26%, 95%, 79%, 64% for CE-CT, 19%, 98%, 89%, 63% for EUS, and 12%, 95%, 63%, 60% for 68 Ga-DOTATOC PET, respectively. Radiologic tumor size >4cm and the presence of radiologic N+ at ≥1 imaging were independent predictors of N+ at pathology. The identification of N+ at ≥1 imaging technique was associated with a higher number of positive LNs compared with negative imaging (4 vs 2) ( P =0.012). CE-CT, EUS, and 68 Ga-DOTATOC PET are poorly sensitive in predicting nodal status in NF-PanNETs despite a high specificity.

Sporadic nonfunctional pancreatic neuroendocrine tumors: Risk of lymph node metastases and aggressiveness according to tumor size: A multicenter international study

BackgroundAlthough the correlation between tumor size and aggressiveness is clearly established in sporadic nonfunctional pancreatic neuroendocrine tumors, the management of tumors ≤2 cm remains debated. In recent guidelines, the cut-off size to operate ranged from 1 to 2 cm. The aim of this retrospective study was to report the rate of lymph nodes metastases in resected sporadic nonfunctional pancreatic neuroendocrine tumors, according to tumor size and, second, to identify risk factors of lymph node metastases and disease-free survival. MethodsResected sporadic nonfunctional pancreatic neuroendocrine tumors from 9 international expert centers were included (1999–2017). Functional pancreatic neuroendocrine tumors, genetic syndromes, and R2 resection were excluded. Aggressiveness was defined as microvascular invasion, perineural invasion, lymph node metastases, G3 grading, distant metastases, and/or recurrence. ResultsOverall, 495 resected sporadic nonfunctional pancreatic neuroendocrine tumors were included. For tumors up to 5 cm, the risk of lymph node metastases was increased by 1.73 for every 1 cm increase in size (odds ratio = 1.73; 95% confidence interval = 1.46–2.03). Tumor size >2 cm (P < .001), perineural invasion (P = .002), microvascular invasion (P < .001), and distant metastases (P = .008) were independently associated with lymph node metastases. Tumor size >2 cm (P = .003), R1 status (P = .004), lymph node metastases (P < .001), and World Health Organization grade 3 (P = .002) were independently associated with disease-free survival. Aggressiveness rate was 13.1% in tumors ≤1 cm and 29% in tumors between 1.1 and 2 cm. ConclusionIn resected sporadic nonfunctional pancreatic neuroendocrine tumors, the risk of lymph node metastases is correlated to tumor size. Considering that sporadic nonfunctional pancreatic neuroendocrine tumors between 1.1 and 2 cm had a higher risk of lymph node metastases and recurrence compared to tumors ≤1 cm, the decision to perform surgery in this subgroup of patients should be individualized in surgically fit patients.

Clinical features and postoperative survival in patients with sporadic versus multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: An international cohort study

BackgroundThe optimal surgical management of pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 is controversial. This study sought to compare clinicopathologic characteristics and outcomes of multiple endocrine neoplasia type 1–associated and sporadic pancreatic neuroendocrine tumors from a large multi-national database. MethodsA multi-institutional, international database of patients with surgically resected pancreatic neuroendocrine tumors was analyzed. The cohort was divided into 2 groups: those with multiple endocrine neoplasia type 1 versus those with sporadic disease. Clinicopathologic comparisons were made. Overall and disease-free survival were analyzed. Propensity score matching was used to reduce bias. ResultsOf 651 patients included, 45 (6.9%) had multiple endocrine neoplasia type 1 and 606 sporadic pancreatic neuroendocrine tumors. Multiple endocrine neoplasia type 1–associated pancreatic neuroendocrine tumors were more common in younger patients and associated with multifocal disease at the time of surgery and higher T-stage. Lymph node involvement and the presence of metastasis were similar. Total pancreatectomy rate was 5-fold higher in the multiple endocrine neoplasia type 1 cohort. Median survival did not differ (disease-free survival 126 months multiple endocrine neoplasia type 1 vs 198 months sporadic, P > .5). After matching, survival remained similar (overall survival not reached in either cohort, disease-free survival 126 months multiple endocrine neoplasia type 1 vs 198 months sporadic, P > .5). Equivalence in overall survival and disease-free survival persisted even when patients who underwent subtotal and total pancreatectomy were excluded. ConclusionMultiple endocrine neoplasia type 1–associated pancreatic neuroendocrine tumors are more common in younger patients and are associated with multifocality and higher T-stage. Survival for patients with multiple endocrine neoplasia type 1–associated pancreatic neuroendocrine tumors is comparable to those with sporadic pancreatic neuroendocrine tumors, even in the absence of radical pancreatectomy. Consideration should be given to parenchymal-sparing surgery to preserve pancreatic function.

Sporadic and Von Hippel-Lindau disease-related pancreatic neuroendocrine tumors definitions are not consistent between the various classification criteria

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

Comparison of clinical features between sporadic pancreatic neuroendocrine tumors and those associated with multiple endocrine neoplasia type 1

Objective: To compare the clinical features of multiple endocrine adenoma type 1 (MEN-1) associated pancreatic neuroendocrine neoplasms (pNENs) as well as sporadic pNENs. Methods: The clinical data of 28 sporadic pNENs patients and 10 MEN-1-related pNENs patients admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to June 2021 were collected. Meanwhile, by searching PubMed database and reviewing the clinical data of 20 foreign patients with MEN-1-related pNENs which were reported at the same time.Compare and analyze the similarities and differences between MEN1-associated pNENs and sporadic pNENs in clinical features, such as family history, blood tests, pathological diagnostic indicators, tumor grade, stage and metastasis, treatment and prognosis and so on. Results: A total of 58 pNENs patients were included, and there were 30 MEN1-related pNENs patients and 28 sporadic pNENs patients. Eighteen patients (60%) had a family history of MEN1-related pNENs, and the mean age of onset was (35.3±13.0)years. There were no patients (0) with family history of sporadic pNENs, and the mean age of onset was(55.3±13.4)years. In contrast, the differences in family history, age of onset and NSE were statistically significant(all P<0.05).Among the pathological diagnostic indicators, there were 19 patients (63.3%) with Grade G2 of MEN1-related pNENs, and 25 patients (83.3%) with somatostatin receptor 2(SSTR2) negative. In sporadic pNENs, there were 16 patients (57.1%) with Grade G2 and 9 patients (32.1%) with SSTR2 negative. The differences in pathological grade, immunohistochemistry (Chromogranin A, CD56, and somatostatin receptor 2, SSTR2) between the two groups were statistically significant(all P<0.05). In terms of tumor staging and metastasis, 21 patients with MEN-1-related pNENs had metastasis (70%) and 20 patients with stage Ⅰ and Ⅱ AJCC (71%) in all. Eight patients with sporadic pNENs had metastasis (26.7%) and 8 patients were with stage Ⅰ and Ⅱ AJCC (28.6%). By contrast, the differences in total metastasis rate, AJCC stage and distant metastasis between the two groups were statistically significant(all P<0.05). In terms of treatment and prognosis, there was no statistical significance in the differences between surgical treatment and prognosis (P>0.05), and the difference was also not statistically significant in survival rate between them (P>0.05). Conclusions: There are no significant differences between MEN1-related pNENs and sporadic pNENs in terms of treatment, prognosis, and survival rate, but there are significant differences in clinical features, pathological features and the staging and grading of tumors. The rate of tumor grade, stage and metastasis of sporadic pNENs is higher.

Is non-operative management of small asymptomatic sporadic nonfunctioning pancreatic neuroendocrine tumors safe?

Is non-operative management of small asymptomatic sporadic nonfunctioning pancreatic neuroendocrine tumors safe?

Surgical Resection of Sporadic Pancreatic Neuroendocrine Tumors: A Two-Decade Experience at a Large Volume Cancer Center

Introduction: Neuroendocrine tumors (NET) are indolent, although an estimated 50% of patients present with metastatic disease. Surgical resection may be reasonable in well-selected patients at every disease stage; but for patients with pancreatic NETs (PNETs), operative risk must be carefully balanced with the risk of progression or recurrence. The objective of this study was to determine post-pancreatectomy long-term outcomes in PNET patients undergoing resection. Methods: From 2000-2020, clinicopathologic information was collected for patients undergoing resection for sporadic PNETs (inherited PNETs excluded) at a large volume cancer center. Surgical complications were prospectively tracked (from 2011) using the Modified Accordion Grading System (MAGS; Major Complication:Grade≥3). Results: Among 392 resected PNET patients, 52.6% were male with a median age of 57 years (IQR:48-66). Twenty percent of patients presented with metastatic disease. Operations performed included enucleation (7.7%), distal pancreatectomy (56.9%), central pancreatectomy (4.3%), pancreaticoduodenectomy (30.1%), and total pancreatectomy (1.0%). Median tumor size was 3 cm (IQR:1.9-5.0), with an R0 resection rate of 90.8%. Twenty-nine percent of all patients had a major complication, (Table). Concurrent hepatic metastatectomy was performed in 12% of patients with a major complication rate of 7.1%. Median overall survival (OS) of all patients was 171 months. Nonmetastatic PNET patients had improved OS compared to metastatic patients (179 months vs.103 months, p<0.001, Figure). Conclusion: PNET resection is safe and can be associated with prolonged survival. Further, resection of the primary PNET and associated metastatic disease is not associated with increased morbidity in selected patients and may achieve long-term survival.Tabled 1Perioperative VariableNumber% / IQRLength of Stay (days, median)86-11Readmission3623.1Any Complication11875.6MAG≥34629.5Delayed Gastric Emptying2012.8Pancreatic Fistula7346.8Postoperative Transfusion127.7Pulmonary Embolism31.9Myocardial Infarction10.6 Open table in a new tab

Multifocality is not associated with worse survival in sporadic pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (pNETs) in patients with hereditary cancer syndromes are typically multifocal. In contrast, sporadic pNETs are usually unifocal and the incidence of multifocal sporadic pNETs is unknown. The primary aim of this study was to investigate the incidence of multifocality in sporadic pNETs and any associated effect on recurrence risk and survival. Patients who underwent resection of pNETs at Mayo Clinic from 2000 to 2019 were identified and clinical data were obtained from medical records. Syndromic disease was defined as pNETs arising in the setting of a hereditary cancer syndrome. Statistical comparisons were made using χ2 , Fisher's exact, and Kruskal-Wallis tests and survival was assessed using the Kaplan-Meier method. Six hundred and sixty-one patients with sporadic pNETs and fifty-nine with syndromic pNETs were identified. Multifocal disease was present in 4.8% of sporadic patients and 84.7% of syndromic patients (p < .001). Within patients with sporadic pNETs, clinicopathologic features and recurrence-free and overall survival were similar between patients with unifocal and multifocal disease. Multifocal sporadic pNETs are rare and multifocality is not associated with worse survival or increased recurrence risk. Patients with multifocal sporadic pNETs can likely be safely managed with a combination of resection and observation as indicated for each tumor.

Impact of Pancreatic Neuroendocrine Tumor on Mortality in Patients With von Hippel-Lindau Disease

ObjectiveThe main causes for morbidity and mortality in von Hippel-Lindau (VHL) disease are central nervous system hemangioblastoma and clear cell renal cell carcinoma, but the effect of VHL-related pancreatic neuroendocrine tumors (PNET) on patient outcome is unclear. We assessed the impact of PNET diagnosis in patients with VHL on all-cause mortality (ACM) risk. MethodsWe used the Surveillance, Epidemiology, and End Results database. Of 16 344 patients, 170 had VHL based on clinical diagnostic criteria, and 510 patients had PNET (91 VHL-related and 419 sporadic). ResultsSurvival analysis demonstrated a lower ACM among patients with VHL-related PNET compared to patients with sporadic PNET (log-rank test, P = .011). Among patients with VHL, ACM risk was higher with vs without PNET (P = .029). The subgroup analysis revealed a higher ACM risk with metastatic PNET (sporadic P = .0031 and VHL-related P = .08) and a similar trend for PNET diameter ≥3 cm (P = .06 and P = 0.1 in sporadic and VHL-related PNET, respectively). In a multivariable analysis of patients with VHL, diagnosis with PNET by itself was associated with a trend of lower risk for ACM, while presence of metastatic PNET was independently associated with increased ACM risk. ConclusionDiagnosis with PNET is not associated with a higher ACM risk in VHL by itself. The independent association of advanced PNET stage with higher mortality risk emphasizes the importance of active surveillance for detecting high-risk PNET at an early stage to allow timely intervention.