Pancreatic Neuroendocrine Tumors Research Articles

DAXX is associated with early recurrence of pancreatic neuroendocrine tumors after R0 resection

IntroductionATRX, DAXX, MEN1, and PTEN mutations are proposed drivers of pancreatic neuroendocrine tumor tumorigenesis and independent prognostic factors for metastasis and mortality. However, their implications after R0 resection remain debated. Thus, we sought to identify genomic signatures of pancreatic neuroendocrine tumor disease-specific mortality and recurrence after surgery for curative intent. MethodsPancreatic neuroendocrine tumor patients who underwent whole exome sequencing with available survival data were identified using cBioPortal. Clinicopathologic variables, genomics, and outcomes were analyzed. ResultsSeventy patients who underwent R0 resection were identified. Forty-five of 70 patients were disease free at last follow-up, whereas 25 of 70 patients had disease-specific mortality or recurrent disease and therefore were categorized as part of the recurrent cohort. There were no significant differences in age (P = .245), sex (P = .201), or median follow-up (38.9 vs 33.7 months, P = .122) between groups. Clinicopathologically, the recurrent cohort had significantly greater tumor size (median 5.0 cm vs 3.2 cm, P = .012) and were more likely to have vascular invasion (88% vs 40%, P = .000), positive lymph nodes (68.0% vs 35.6%, P = .013), and metastatic disease (44% vs 4.4%, P < .000). For both cohorts, most tumors were well or moderately differentiated. Tumor mutation burden was greater in the recurrent cohort (median 0.77 vs 0.43 mutations/Mb, P = .004). DAXX mutations were more frequent in the recurrent cohort (36% vs 11%, P = .026) and in those with vascular invasion (51% vs 92%, P = .010). ConclusionOur analysis demonstrated the prognostic significance of DAXX mutations after curative-intent surgery. Future studies investigating DAXX mutations as a biomarker for aggressive features to guide treatment are warranted.

The evolutionary history of metastatic pancreatic neuroendocrine tumours reveals a therapy driven route to high-grade transformation.

Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high-grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high-grade disease. We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post-alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with MEN1 inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high-grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden >50 (50%). In comparison, among the eight patients who did not show high-grade progression, 0 had a tumour mutational burden >50 (0%; odds ratio 'infinite', 95% confidence interval 1.8 to 'infinite', p = 0.02). Our findings contribute to broaden the understanding of metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

S1559 Efficacy and Safety of EUS-RFA in Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

S1559 Efficacy and Safety of EUS-RFA in Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

S2675 Pancreatitis and Obstructive Jaundice as Presenting Symptoms for Ampullary Pancreatic Neuroendocrine Tumor

S2675 Pancreatitis and Obstructive Jaundice as Presenting Symptoms for Ampullary Pancreatic Neuroendocrine Tumor

S2661 A Case of Pancreatic Neuroendocrine Tumor Recurrence and Development of Type 3c diabetes

S2661 A Case of Pancreatic Neuroendocrine Tumor Recurrence and Development of Type 3c diabetes

S2478 Negative Does Not Mean No: Exercising Persistence in the Evaluation of a Pancreatic Neuroendocrine Tumor

S2478 Negative Does Not Mean No: Exercising Persistence in the Evaluation of a Pancreatic Neuroendocrine Tumor

S2470 Diagnosis of Non-Functional Pancreatic Neuroendocrine Tumor in a Patient with a Transplanted Pancreas: A Case Report

S2470 Diagnosis of Non-Functional Pancreatic Neuroendocrine Tumor in a Patient with a Transplanted Pancreas: A Case Report

Adrenaline bolus rescue for refractory carcinoid crises during surgical manipulation of metastatic neuroendocrine tumor of pancreas: A case report

Carcinoid crisis is a potentially fatal condition with severe hemodynamic instability. A 25-year-old female with metastatic pancreatic neuroendocrine tumor with recurrent carcinoid crises was posted for surgical debulking. Intraoperatively, the patient was on crisis during manipulation of the lesion by the surgeon, which was unresponsive to octreotide, infusions of phenylephrine, and norepinephrine agents. The patient was then effectively managed with adrenaline blouses at 10 µg along with infusion of adrenaline. Use of inotropes and vasopressors is not encouraged in carcinoid due to release of inflammatory mediators which can precipitate the hemodynamic instability. Here, we managed her with adrenaline boluses and infusion.

S1614 Grading of Pancreatic Neuroendocrine Tumors by EUS FNA/FNB: A Tertiary Care Center Experience

S1614 Grading of Pancreatic Neuroendocrine Tumors by EUS FNA/FNB: A Tertiary Care Center Experience

Gastroenteropancreatic neuroendocrine neoplasms: epidemiology, genetics, and treatment.

The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) is increasing at a rapid pace and is becoming an increasingly important consideration in clinical care. Epidemiological data from multiple countries indicate that the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibits regional, site-specific, and gender-based variations. While the genetics and pathogenesis of some GEP NEN, particularly pancreatic NENs, have been investigated, there are still many mechanisms that require further investigation. The management of GEP NEN is diverse, but surgery remains the primary option for most cases. Peptide receptor radionuclide therapy (PRRT) is an effective treatment, and several clinical trials are exploring the potential of immunotherapy and targeted therapy, as well as combination therapy.

Misdiagnosis of pancreatic intraductal papillary mucinous neoplasms and the challenge of mimicking lesions: imaging diagnosis and differentiation strategies.

The rising prevalence of pancreatic cystic lesions (PCLs), particularly intraductal papillary neoplasms (IPMNs), has been attributed to increased utilization of advanced imaging techniques. Incidental detection of PCLs is frequent in abdominal CT and MRI scans, with IPMNs representing a significant portion of these lesions. Surveillance of IPMNs is recommended due to their malignant potential; however, their overlapping imaging features with benign entities can lead to misdiagnosis, overtreatment, and overutilization of healthcare resources. This paper aims to highlight and differentiate lesions often mistaken for IPMNs, providing insight into their imaging characteristics, diagnostic challenges, and distinctive features while highlighting the incidence of wrong diagnosis for these lesions. These lesions include serous cystadenomas, cystic pancreatic neuroendocrine tumors, mucinous cystic neoplasms, lymphoepithelial cysts, duodenal diverticula, pancreatic schwannomas, chronic pancreatitis, retention cysts, intrapancreatic accessory spleens, pancreatic lipomas, choledochal cysts, and others. Utilizing various imaging modalities, including contrast-enhanced CT, MRI, and EUS, alongside histological and molecular analyses, can aid in accurate diagnosis and appropriate management. Understanding these mimicry scenarios is crucial to avoid unnecessary surveillance, interventions, and the burden they place on both patients and healthcare systems. Improved recognition of these lesions can lead to better patient outcomes and resource allocation.

Deep learning and automatic differentiation of pancreatic lesions in endoscopic ultrasound - a transatlantic study.

Endoscopic ultrasound (EUS) allows characterization and biopsy of pancreatic lesions. Pancreatic cystic neoplasms (PCN) include in mucinous (M-PCN) and non-mucinous lesions (NM-PCN). Pancreatic ductal adenocarcinoma (P-DAC) is the commonest pancreatic solid lesion (PSL), followed by pancreatic neuroendocrine tumor (P-NET). While EUS is preferred for pancreatic lesion evaluation, its diagnostic accuracy is suboptimal. This multicentric study aims to develop a convolutional neural network (CNN) for detecting and distinguishing PCN (namely M-PCN and NM-PCN) and PSL (particularly P-DAC and P-NET). A CNN was developed with 378 EUS exams from 4 international reference centers (Centro Hospitalar Universitário São João, Hospital Universitario Puerta de Hierro Majadahonda, New York University Hospitals, Hospital das Clínicas FMUSP). 126.000 images were obtained - 19.528 M-PCN, 8.175 NM-PCN, 64.286 P-DAC, 29.153 P-NET and 4.858 normal pancreas images. A trinary CNN differentiated normal pancreas tissue from M-PCN and NM-PCN. A binary CNN distinguished P-DAC from P-NET. The total dataset was divided in a training and testing dataset (used for model's evaluation) in a 90/10% ratio. The model was evaluated through its sensitivity, specificity, positive and negative predictive values and accuracy. The CNN had 99.1% accuracy for identifying normal pancreatic tissue, 99.0% and 99.8% for M-PCN and NM-PCN, respectively. P-DAC and P-NET were distinguished with 94.0% accuracy. Our group developed the first worldwide CNN capable of detecting and differentiating the commonest PCN and PSL in EUS images, using exams from 4 centers in two continents, minimizing the impact of the demographic bias. Larger multicentric studies are needed for technology implementation.

Long-term experience with octreotide and lanreotide for the treatment of gastroenteropancreatic neuroendocrine tumors.

The somatostatin analogs (SSA) octreotide and lanreotide are a mainstay in the treatment of neuroendocrine tumors (NET). The two pivotal trials differed considerably in terms of patient characteristics and are not directly comparable. Further comparative data are lacking. This retrospective chart review study included patients with gastroenteropancreatic NET grade 1 or 2 who were treated with octreotide LAR or lanreotide autogel. The main aim was to compare the two SSA based on progression-free survival (PFS) and overall survival (OS) from treatment start. In total, 129 patients were analyzed, 60% (n = 77) had a small intestinal NET and 31% (n = 40) a pancreatic NET. Histologically, 34% (n = 44) had NET G1, 55% (n = 71) a NET G2, and 11% (n = 14) a NET G1/G2 unclassified. Lanreotide was used in 90 patients (70%) and octreotide in 39 patients (30%). Overall, the median PFS was 32.2months (95%CI 23.0-42.9months). No PFS difference (p = 0.8) was observed between lanreotide (29.8months, 95%CI 18.7-48.5months) and octreotide (36.0months, 95%CI 23.2-68.2months). Median OS from treatment start was calculated at 93.5months (95%CI 71.1-132.9months). Again, the median OS following lanreotide (113.4months, 95%CI 62.3-NA months) or after octreotide (90.3months, 95%CI 71.1-NA months) did not differ significantly (p > 0.9). Our long-term experience with octreotide and lanreotide in NET did not reveal differences in antitumor effectiveness. This is consistent with previous reports and might suggest that both SSA can be used interchangeably if needed.

The value of a nomogram model based on CT imaging features in differentiating duodenal gastrointestinal stromal tumors from pancreatic head neuroendocrine tumors

The value of a nomogram model based on CT imaging features in differentiating duodenal gastrointestinal stromal tumors from pancreatic head neuroendocrine tumors

Laparoscopic Central Pancreatectomy with Modified Blumgart Pancreatojejunostomy for Pancreatic Neuroendocrine Tumor.

This report with a video describes a laparoscopic central pancreatectomy with modified Blumgart pancreatojejunostomy for pancreatic neuroendocrine tumor. A 71-year-old woman presented with a single 17 mm lesion in the pancreatic neck, responsible for dilatation of the main pancreatic duct. Cancer staging showed no additional location. Somatostatin receptor imaging was positive. After a multidisciplinary discussion in the French national reference network for the management of neuroendocrine tumor (RENATEN) surgery with central pancreatectomy was decided. The operation time was 320 min and the estimated blood loss was less than 100 ml. Final pathology confirmed a pancreatic NET of 13 mm staged as T1 N0 M0 R0 G1 with a Ki-67 of 2%. After lymph node dissection, five nodes were analyzed and were found to be noninvaded. The postoperative course was uneventful. Laparoscopic central pancreatectomy is an excellent alternative for sparing pancreatic parenchyma.

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.

Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear. We enrolled two independent cohorts of patients - those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors - who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety. In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events. Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib. (Funded by the National Cancer Institute and others; CABINET ClinicalTrials.gov number, NCT03375320.).

Transformation of non-functioning pancreatic neuroendocrine tumours into insulinomas in multiple endocrine neoplasia type 1: a case report

Transformation of non-functioning pancreatic neuroendocrine tumours into insulinomas in multiple endocrine neoplasia type 1: a case report

Refractory hypercalcaemia in advanced metastatic pancreatic neuroendocrine tumour controlled on weekly denosumab

Refractory hypercalcaemia in advanced metastatic pancreatic neuroendocrine tumour controlled on weekly denosumab

Abstract B032: Evaluating T cell-inflammation in pancreatic neuroendocrine tumors

Abstract Background: Pancreatic neuroendocrine tumors (pNETs) are rare tumors arising from neuroendocrine cells in the pancreas. Their clinical behaviour and prognosis are variable and durable responses are often difficult to achieve with conventional therapies. Immunotherapy approaches may be efficacious in a subgroup of pNETs. In a recent study that did not include pNETs, we showed that a four-chemokine signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) predicts T cell-inflammation and response to immune checkpoint inhibitors across cancers. We have hypothesized that the c-Score will also identify pNET subgroups with T cell-inflammation. Methods: The c-Score and hallmarks of the cancer-immunity cycle are being evaluated in pNETs as a cohort study (n=100 cases) of the Marathon of Hope Cancer Centres Network whole genome and transcriptome tumor sequencing (WGTS) project. The cohort study will compare pNET profiles with those of other pancreatic and peri-ampullary tumors. Results: As of June 1, 2024, primary tumor data from 23 cases were available for analysis, including 16 pNETs, 2 pancreatic ductal adenocarcinomas (PDAC), 2 pancreatic adenosquamous carcinoma (PASC), 2 distal cholangiocarcinomas (dCCA), and 1 ampullary carcinoma (AC). Dimension reduction by principle component analysis (PCA) revealed clustering based on histological subtype. Interestingly, PCA using immune genes also demonstrate subgrouping that overlapped with the histological subtypes, suggesting that immunity of pancreatic/peri-ampullary neoplasms may be directed by histological types rather than the pancreas gland itself. These cancers showed a broad distribution of c-Score expression, with pNETs having the lowest c-Score. Tumors with high expression of the c-Score, including 2 pNETs, had increased expression of cancer-immunity cycle gene sets. DUX4, FAM186A, and IGFN1 were amongst the most common genes mutated in all tumors. Conclusions: Early data suggest that pNETs generally harbor low c-Score values and hallmarks of cancer-immunity, with the existence of a subgroup of pNETs displaying T cell-inflammation. Citation Format: Joan Miguel Romero, James Vafiadis, Tess Aalto, Ruomeng Fang, Yifan Wang, George Zogopoulos. Evaluating T cell-inflammation in pancreatic neuroendocrine tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B032.

Robotic single-port plus one-port splenic vessel-conserving spleen-preserving distal pancreatectomy: a case report.

Minimally invasive distal pancreatectomy is a safe and effective surgical approach for the treatment of distal pancreatic tumors. Recently, the da Vinci single-port (SP) system (Intuitive Surgical, Inc.) was introduced to overcome the previously known limitations of this approach. Here, we report our experience with robotic SP plus one-port splenic vessel-conserving spleen-preserving distal pancreatectomy (RSP + 1 SVc-SpDP). A 38-year-old male patient was incidentally found to have a pancreatic neuroendocrine tumor. On May 12, 2023, RSP + 1 SVc-SpDP was performed. The robotic SP was placed at the transumbilical site, and an additional 12-mm port was placed on the left side of the patient's abdomen. The surgical procedure was based on splenic vessel-conserving, spleen-preserving distal pancreatectomy. The operative time was 350 minutes, and the patient was discharged on postoperative day 8 without any complications. The initial experience of RSP + 1 SVc-SpDP using the da Vinci SP system showed the possibility of an alternative operation for distal pancreatectomy.