Nonfunctioning Pancreatic Neuroendocrine Tumors Research Articles

CUX1-Transcriptional Master Regulator of Tumor Progression in Pancreatic Neuroendocrine Tumors.

Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts (n = 43 and n = 141 tissues) of non-functional treatment-naïve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months; p = 0.005). In treatment-naïve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months; p = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.

Functionality is not an independent prognostic factor for pancreatic neuroendocrine tumors.

BACKGROUNDPancreatic neuroendocrine neoplasms (pNENs) that produce hormones leading to symptoms are classified as functional tumors, while others are classified as nonfunctional tumors. The traditional view is that functionality is a factor that affects the prognosis of pNEN patients. However, as the sample sizes of studies have increased, researches in recent years have proposed new viewpoints.AIMTo assess whether functionality is an independent factor for predicting the prognosis of pNEN patients.METHODSFrom January 2004 to December 2016, data of patients who underwent surgery at the primary site for the treatment of pNENs from the Surveillance, Epidemiology, and End Results (SEER) database and West China Hospital database were retrospectively analyzed.RESULTSContemporaneous data from the two databases were analyzed separately as two cohorts and then merged as the third cohort to create a large sample that was suitable for multivariate analysis. From the SEER database, age (P = 0.006) and T stage (P < 0.001) were independent risk factors affecting the survival. From the West China Hospital database, independent prognostic factors were age (P = 0.034), sex (P = 0.032), and grade (P = 0.039). The result of the cohort consisting of the combined populations from the two databases showed that race (P = 0.015), age (P = 0.002), sex (P = 0.032) and T stage (P < 0.001) were independent prognostic factors. In the West China Hospital database and in the total population, nonfunctional pNETs and other functional pNETs tended to have poorer prognoses than insulinoma. However, functionality was not associated with the survival time of patients with pNETs in the multivariate analysis.CONCLUSIONFunctionality is not associated with prognosis. Race, age, sex, and T stage are independent factors for predicting the survival of patients with pNETs.

Development of a non-functional pancreatic neuroendocrine tumor and a duodenal ulceration after cholecystoduodenostomy in a cat

A six-year-old Ragdoll with previous extrahepatic biliary tract obstruction due to cholangiohepatitis, treated with cholecystoduodenostomy, was presented for acute vomiting, hyporexia, and weight loss. Abdominal ultrasound examination revealed randomly distributed hepatic nodules and dilated biliary ducts. Gastroduodenoscopy showed a patent cholecystoduodenostoma but disclosed a perforated duodenal ulceration. Conversion to celiotomy revealed extensive liver pathology, a discrete pancreatic nodule, and a duodenal ulcer opposite to the cholecystoduodenostoma. The cat was euthanized intra-operatively and necropsy was performed. The intrahepatic biliary tract of the right liver lobes was obstructed and severely dilated, whereas bile from the left lobes drained through the cholecystoduodenostoma. Histopathologic diagnoses were a primary pancreatic tumor, positive for glucagon on immunohistochemistry, with liver metastases, chronic purulent cholecystitis, and duodenal ulceration. To the authors’ knowledge, this is the first report in which the development of pancreatic neoplasia is described in a cat with a history of biliary tract disease.

Predicting survival in non-functional pancreatic neuroendocrine tumours.

Owing to the limited prevalence and heterogeneity, it is difficult to predict long-term survival of non-functional pancreatic neuroendocrine tumours (NF-PNETs).This study aimed to evaluate the factors predicting disease-specific survival (DSS) for well-differentiated NF-PNETs. Data were collected retrospectively from 256 patients with pancreatic neuroendocrine tumours who underwent surgical resection between January 2009 and December at our institution. Of these, 103 NF-PNETs (40%) were identified for analysis. Of the 103 patients, 54 were male (52%) and the mean age was 52 years (range 21-75 years). Most patients (60/103, 58%) in our series were symptomatic. Seventeen patients (16%) died during follow-up, with a median period of 47 months. There were 88 patients with well-differentiated tumours and 10 of them (10/88, 11%) died of tumour progression. Median DSS after primary resection was 58.8 months (range 16-122 months). Multivariate analysis identified age >52 years (P = 0.038) and tumour grade G2 (P = 0.001) as statistically significant predictors of DSS. There was no association between gender, tumour size, symptoms, surgical procedure, severe complications, tumour location, tumour size, resection margin, positive lymph nodes and vascular invasion with DSS. Tumour grade, age, presence of symptoms and distant metastasis were related to poor DSS of NF-PNETs. Age >52 years and tumour grade G2 might be independent predictors of poor DSS for patients with well-differentiated NF-PNETs.

Prognostic Role of Examined and Positive Lymph Nodes after Distal Pancreatectomy for Non-Functioning Neuroendocrine Neoplasms

Background: The most appropriate nodal staging system for non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) remains unclear. Despite some evidence is available for pancreaticoduodenectomy, the adequate nodal staging is still unknown for distal pancreatectomy (DP). The aim of the present study was to evaluate the prognostic impact of the number of positive lymph nodes (PLNs) after DP for NF-PanNETs and to define the minimal number of lymph nodes to be harvested for an appropriate nodal staging. Methods: Data were retrospectively collected from patients who underwent DP with curative intent (R0-R1) for sporadic well-differentiated NF-PanNETs in 4 European high-volume centres. NF-PanNETs with nodal involvement (N+) were subclassified into N1 (1–3 PLNs) and N2 (4 or more PLNs). Univariate and multivariate analyses of disease-free survival (DFS) were performed. Results: Of 271 patients in the study, 62 (23%) had nodal involvement (N+). A higher probability of N+ was associated with the following factors: grading, resection margin status, perineural and microvascular invasion, and the number of examined lymph nodes. Three-year DFS rate for N0, N1, and N2 patients was 92, 72, and 50%, respectively (p < 0.001). At multivariate analysis, independent predictors of DFS were grading, T stage, presence of necrosis, and nodal status. For patients with ≥12 examined/resected lymph nodes, the N status remained a significant predictor of disease recurrence (p < 0.001), while it failed to predict recurrence in patients with <12 lymph nodes examined/resected (p = 0.116). Conclusions: A minimal number of 12 nodes should be harvested in case of DP for NF-PanNET for an appropriate nodal staging. The number of positive lymph nodes is an independent predictor of DFS after DP for NF-PanNET, and the N0/N1/N2 nodal classification seems to be more relevant than the current N0/N+ staging.

Analysis of recurrence after resection of well-differentiated non-functioning pancreatic neuroendocrine tumors.

Although pancreatic neuroendocrine tumors (PNETs) are generally considered to have a favorable overall prognosis after resection, disease recurrence has been observed. Few studies have specifically addressed recurrence after resection of PNETs, especially for non-functioning PNETs (NF-PNETs). The aim of our study is to analyze the recurrence of resected well-differentiated NF-PNETs.Patients who underwent surgical resection for grade 1 and 2 NF-PNETs without synchronous metastasis were identified for analysis. Patients were treated from January 2009 to December 2017 in our institution. Univariate and multivariate cox regression analysis were conducted to identify prognostic factors.Of the 88 patients, 46 were men (52%) and the mean age was 52 years. With a median follow-up of 49.1 months (range, 8–122 months), there were 12 recurrences (14%). Liver was the most common recurrence site (7/12, 58%). The 1-, 3-, and 5-year recurrence-free survival was 99%, 90%, and 88%, respectively. Univariate analysis identified that age >52 years, positive lymph nodes, tumor grade 2, and Ki67 index ≥5% were statistically significant. Multivariate analysis identified that Ki67 index ≥5% (hazard ratio [HR], 4.69; 95% confidence interval [CI], 1.36–16.75, P = .015), positive lymph nodes (HR, 6.75; 95% CI, 1.73–24.43, P = .006) were independently associated with recurrence. The 5-year disease-free survival rate was 53% (95% CI, 14.20–91.81%) for patients with Ki-67 ≥5% or (and) positive lymph nodes, while 95% (95% CI, 82.26–100%) for the patients without these 2 factors.Ki67 index and lymph node status are independently associated with recurrence after resection of well-differentiated NF-PNETs in this study.

Surgical treatment of non-functioning pancreatic neuroendocrine tumors: current controversies and challenges

Abstract There has been a rising trend in the incidence and prevalence of non-functioning pancreatic neuroendocrine tumors (NFPanNETs). While a significant number of the newly diagnosed NFPanNETs are asymptomatic, a majority of patients will present with liver metastasis (LM) at the time of diagnosis. Surgical resection remains the only curative treatment, especially for localized NFPanNETs. While a majority of small NFPanNETs are indolent, some are not. This heterogeneity in tumor biology presents the surgeon with the unique challenge of determining which patient will benefit from surgery, given the morbidity of pancreatic surgery. There has been a recent push for a more aggressive approach to the care of these patients, given the emergence of data supporting such measures. However, the risk of over or under treatment has generated immense debate amongst experts in the field. The heterogeneity of current practice guidelines and institutional practices around the world is a reflection of the disparate opinion on the management of NFPanNET. In this review, we set out to examine the evidence regarding some of the most controversial and challenging aspects of the surgical treatment of NFPanNET. We evaluate the following questions; should patients with small NFPanNETs ≤ 2 cm in size be resected; should patients with metastatic NFPanNETs undergo surgical debulking, and should there be resection of the primary tumor in the setting of non-resectable metastatic disease? Although there are currently no Level 1 data to answer these questions conclusively, we believe that the current literature supports a more aggressive approach to the management of NFPanNET.

Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature.

Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.

A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms: An International Multicenter Cohort Study.

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off ≥0.2 mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size ≥3.0 cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p < 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival.

SUN-124 Are Venous Thromboembolic Events Increased in MEN1 Patients?

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder in which patients develop multiple simultaneous hormone-secreting tumors. Most common tumors include: anterior pituitary adenomas (50%), multi-gland parathyroid adenomas (95%), and gastroenteropancreatic neuroendocrine tumors (40-80%). Only rare MEN1 associated glucagonomas (<1%), and ACTH-producing neuroendocrine tumors (<5%) are known to increase risk of hypercoagulability. It is unknown if patients with MEN1 syndrome have increased risk of venous thrombolytic events (VTE), defined as a deep-vein thrombosis and/or pulmonary embolism. Methods: We queried a prospective natural history study of MEN1 patients who tested positive for germline MEN1 mutations (n=287) between 1991-2019 (54 patients on our current protocol were followed before 1991; the earliest was 1971). All lifetime events of VTE were included. Search terms included: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban and apixaban. After initial screening, 10 patients were removed due to insufficient clinical data. Kaplan-Meier analysis was performed to compare age of death between the two cohorts. Results were expressed as mean ± standard deviation. Results: Thirty-four subjects (mean 57.5 years-old, 17 women) were identified with any VTE, yielding a prevalence rate of 13.4%. The incidence of VTE corresponded to 264 events per 100,000 patient-years, which was ~2-fold higher than the estimated annual incidence rate in the general population (104-183/100,000 patient years).1 Kaplan-Meier analysis revealed no significant difference in survival between the two groups (non-VTE cohort mean 81.1 years ± 2.23; VTE cohort mean 77.4 years ± 3.45; p = 0.96). Thirty-two events occurred during the surveillance period at our institution; 9 individuals had more than one VTE. At the time of VTE, 80% had hyperparathyroidism (mean PTH ± SD; 97.56 pg/mL ± 90.76), 21% had hyperprolactinemia (prolactin 25.7μg/L ± 43.41), 62.5% had hypergastrinemia (mean gastrin 1100.9 pg/mL ± 3127.8), and 84.6% had non-functional pancreatic neuroendocrine tumors. One patient was identified to have a Factor V Leiden mutation, 3 patients had lupus anti-coagulant. Eleven patients experienced events within a post-surgical period of 3 months. Conclusions: Hypercoagulability in MEN1 has been previously unidentified. Our cohort data suggests a two-fold increase in the incidence of VTE as compared to the general population, with a high risk occurring within the perioperative period. Further mechanistic investigation and validation from other cohorts are needed to confirm the increased prevalence of VTE in this population. 1Heit, John A., et al. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015 Aug;12(8): 464-474.

MON-922 Multiple Endocrine Neoplasia Type 1- A Clarion Call for Clarity

A 35-year-old gentleman presented with epigastric pain and bilious emesis. He also endorsed urinary frequency, non-bloody diarrhea and diffuse bone pain. On physical examination he had epigastric tenderness and multiple hyperpigmented skin lesions.An abdominal computed tomography (CT) scan revealed multiple diverticula with peri-colonic fat stranding in the descending and sigmoid colon, concerning for diverticulitis. He was started on a course of metronidazole and ciprofloxacin. A 3.1 cm mass was incidentally noted in the uncinate process of the pancreas. Bilateral adrenal nodules were also appreciated.An endoscopic ultrasound (EUS) guided trans-gastric fine needle aspiration biopsy was performed, revealing a well differentiated pancreatic neuroendocrine tumor (pNET - pT3N1Mx, intermediate risk). Chromogranin A was elevated to 108 ng/ml (reference range <93 ng/ml). Serum and urine metanephrine, V-peptide, gastrin, glucagon and parathyroid hormone related peptide were all normal; indicating a nonfunctioning neuroendocrine tumor. He underwent a pancreaticoduodenectomy. Octreotide scan was unrevealing for residual uptake. Adrenal biopsy revealed adrenal adenomas.Three years later, he presented with severe abdominal pain and a new pancreatic mass was noted on CT. Chromogranin A was elevated to 227 ng/mL. EUS revealed a 0.35 cm mass in the bed of the pancreatic head, encasing the superior mesenteric artery. Pathology was positive for recurrence of the neuroendocrine tumor.He was hypercalcemic to 11.4 mg/dL and parathyroid hormone was elevated to 319 pg/mL. CT neck revealed a 0.1 cm nodule concerning for parathyroid adenoma. He underwent a subtotal parathyroidectomy.Genetic testing confirmed Multiple Endocrine Neoplasia Type 1 (MEN1) with a heterozygous mutation of the menin1 gene.MEN1 is a rare genetic syndrome with affected individuals at increased risk of developing pancreatic, pituitary, parathyroid gland and cutaneous tumors. With a kaleidoscope of presentations, clinicians must maintain a high index of suspicion for MEN1, particularly for cases with nonfunctioning pNETs which present insidiously and are the foremost cause of mortality in MEN1 patients.1Further clarity is needed on MEN1 associated pNET prognostic risk stratification, surveillance and targeted immunochemotherapy.2 Timely and algorithmic screening for MEN 1 syndrome in patients with pancreatic incidentalomas is essential to improving patient outcomes.1.Kamilaris CDC, Stratakis CA. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front Endocrinol. 2019;10:339. doi:10.3389/fendo.2019.003392.Yates CJ, Newey PJ, Thakker RV. Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1. Lancet Diabetes Endocrinol. 2015;3(11):895-905. doi:10.1016/S2213-8587(15)00043-1

MON-921 Autonomous Cortisol Secretion Coexisting with Pancreatic Neuroendocrine Tumor: A Rare Presentation

Introduction: neuroendocrine tumors (NET) are a very rare and heterogeneous group of malignancies that can be associated with adrenocortical tumors in approximately 20% of the cases, mostly bilateral and non-functioning. Autonomous cortisol secretion occurs in less than 10% of adrenal incidentalomas and the coexistence of pancreatic neuroendocrine neoplasms and autonomous cortisol secretion is not well-described.Clinical case: a 54-year-old man with previous history of systemic hypertension and type 2 diabetes mellitus, presented with left hypochondrium pain in the last 18 months, associated with abdominal distension, constipation and nausea. Physical examination without abnormalities. Abdominal tomography demonstrated dilatated pancreatic duct and a solid heterogeneous nodule in left adrenal, measuring about 2.7 cm. Ecoendoscopy revealed a heterogeneous, hypoechoic and oval nodular lesion, located at the transition of pancreatic head and uncinate process, measuring 1.5x1.1cm. Biopsy was performed, showing a pattern of neuroendocrine neoplasia, with chromogranin and synaptophysin +, Ki67 1%. Gallium-68 dotatate PET revealed two pancreatic nodular formations, one in proximal neck/body (1.5 cm) and the other in pancreatic tail (1 cm), presenting SUV of 20.4 and 21, respectively. Adrenal nodule presented minimal increase in radiopharmaceutical concentration. To exclude the hypothesis of metastasis, PET FDG was performed, showing physiological uptake in adrenal nodule. Pituitary MRI had no abnormalities.Chromogranin A and gastrin values were normal. Pheochromocytoma and primary hyperaldosteronism were excluded. Hypercortisolism investigation presented the following results: 23h salivary cortisol 167ng/dl (NR < 100), 24-hour free urinary cortisol 42.1 mcg/24h (NR 4.2-60), post-1mg and 2mg dexamethasone serum cortisol of 10.8 mcg/dl and 3.8 respectively (serum dexamethasone levels of 193 and 780 ng/dl; NR > 130), ACTH 13 and 11 pg/ml.By these results, coexistence of non-functioning pancreatic neuroendocrine tumor and autonomous cortisol secretion was confirmed. A total pancreatectomy with partial gastrectomy and bileodigestive anastomosis was performed. Pathological anatomical evidence demonstrated a well-differentiated neuroendocrine tumor (NET G1) and immunohistochemistry analyses showed positive chromogranine A, synaptophysine, Ki67 1% and negative ACTH. Clinical follow-up of the adrenal adenoma was preferred.Conclusion: although most adrenocortical tumors associated with NET are nonfunctional, hypercortisolism should be considered. Adrenal metastasis and ectopic ACTH secretion are differential diagnosis. Clinical follow-up is an option when patient is asymptomatic and comorbidities are well-controlled.

Few comments on “A rational approach to postoperative surveillance for resected non-functional pancreatic neuroendocrine tumors”

Few comments on “A rational approach to postoperative surveillance for resected non-functional pancreatic neuroendocrine tumors”

Surgical resection of primary tumor is associated with prolonged survival in low-grade pancreatic neuroendocrine tumors

The incidence of pancreatic neuroendocrine tumors (PNETs) is increasing over the past few decades. Surgery for low-grade and small PNETs of less than 2cm and N0M0 is still debated. The purpose of this study is to examine the association between surgical resection and survival in patients with low-grade nonfunctioning PNETs. Patients diagnosed with PNETs between 2004 and 2015 were extracted from SEER. Kaplan-Meier methods and Cox proportional hazard models were used to estimate independent predictors in PNETs patients. A total of 2637 patients (2147 underwent surgical resection and 490 did not undergo surgery) with histologically confirmed low-grade PNETs in this cohort study. Overall survival (OS) and cancer-specific survival (CSS) of patients with surgery was better than those without surgery (log rank test POS<0.001, PCSS<0.001). Multivariate Cox regression analysis showed that surgical status was an independent prognostic factor associated with OS (HR 3.257, 95%CI: 2.635, 4.026) and CSS (HR 3.546, 95%CI: 2.798, 4.493). Subgroup analysis suggested the patients receiving surgery apparently had better OS and CSS regardless of tumor size (all log rank test POS<0.001, all log rank test PCSS<0.001) and SEER stage (all log rank test POS<0.001, all log rank test PCSS<0.001), compared to patients without removal of the primary tumor. Surgical resection of primary tumor may have a significant benefit on survival for patients with low-grade nonfunctioning PNETs. To determine the optimal management, grade, stage and tumor size should be considered comprehensively.

Predicting Aggressive Behavior in Nonfunctional Pancreatic Neuroendocrine Tumors With Emphasis on Tumor Size Significance and Survival Trends: A Population-Based Analysis of 1787 Patients.

Nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) are rare tumors with continued controversies in management. This study aims to identify demographic and clinicopathologic characteristics associated with aggressive behavior and survival. The Surveillance, Epidemiology, and End Results database was used to identify patients with NF-PNETs from 1988 to 2012. Multivariate regression analysis and Cox proportional hazards modeling were used to assess the impact of patient, tumor, and treatment characteristics on tumor behavior and overall survival. In 1787 patients identified, size was a major determinant of aggressive behavior. The probability of aggressiveness increased 100% for tumor size ≥2 cm. For tumors ≥2 cm, every 1-cm increase in size was associated with an increase in probability of aggressive behavior by 11.3%. Patient age, tumor grade, and surgical resection were independent predictors of survival. Surgical resection was associated with improved survival but not grade I or II tumors with size <2 cm. Patient age, tumor size, and grade should be in the decision-making process around the surgical management of NF-PNETs. For tumors ≤2 cm with histologic grades of I or II, the probability of aggressive behavior is low, and surgical resection does not appear to afford survival benefit. Therefore, close observation could be justified.

Surgical Principles in the Management of Pancreatic Neuroendocrine Neoplasms.

Pancreatic neuroendocrine neoplasms (PanNENs) are increasingly recognized entities, whose incidence has dramatically grown during the last two decades. Surgery plays a pivotal role in their management as it represents the only chance of cure. Since PanNENs display a wide range of aggressiveness, their surgical management needs to be tailored on tumor's and patient's characteristics. Currently, there are several open questions and burning issues in the field of PanNEN, such as the management of asymptomatic nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET) ≤ 2cm. An active surveillance of these small lesions has been demonstrated to be safe although the available evidences are only based on retrospective studies. On the other hand, formal pancreatic resection associated with lymphadenectomy represents the gold standard for patients with localized NF-PanNEN > 2cm or NF-PanNEN ≤ 2cm in the presence of symptoms, dilation of the main pancreatic duct or suspicion of nodal metastases. Surgery plays also an important role in the setting of metastatic disease. In particular, surgery is generally recommended in the presence of low-grade, resectable, metastatic disease, but several series have reported also a survival benefit of palliative primary tumor resection in patients with unresectable liver metastases. The role of surgery in PanNEN G3 is still controversial. Indeed, surgery is associated with an improved survival in patients with well-differentiated PanNET G3, whereas there is almost no survival benefit in case of poorly differentiated lesions.

Noncontrast Radiomics Approach for Predicting Grades of Nonfunctional Pancreatic Neuroendocrine Tumors.

Endoscopic ultrasound-guided fine-needle aspiration is associated with the accurate determination of tumor grade. However, because it is an invasive procedure there is a need to explore alternative noninvasive procedures. To develop and validate a noncontrast radiomics model for the preoperative prediction of nonfunctional pancreatic neuroendocrine tumor (NF-pNET) grade (G). Retrospective, single-center study. Patients with pathologically confirmed PNETs (139) were included. 3T/breath-hold single-shot fast-spin echo T2 -weighted sequence and unenhanced and dynamic contrast-enhanced T1 -weighted fat-suppressed sequences. Tumor features on contrast MR images were evaluated by three board-certified abdominal radiologists. Multivariable logistic regression analysis was used to develop the clinical model. The least absolute shrinkage and selection operator method and linear discriminative analysis (LDA) were used to select the features and to construct a radiomics model. The performance of the models was assessed using the training cohort (97 patients) and the validation cohort (42 patients), and decision curve analysis (DCA) was applied for clinical use. The clinical model included 14 imaging features, and the corresponding area under the curve (AUC) was 0.769 (95% confidence interval [CI], 0.675-0.863) in the training cohort and 0.729 (95% CI, 0.568-0.890) in the validation cohort. The LDA included 14 selected radiomics features that showed good discrimination-in the training cohort (AUC, 0.851; 95% CI, 0.758-0.916) and the validation cohort (AUC, 0.736; 95% CI, 0.518-0.874). In the decision curves, if the threshold probability was 0.17-0.84, using the radiomics score to distinguish NF-pNET G1 and G2/3, offered more benefit than did the use of a treat-all-patients or treat-none scheme. The developed radiomics model using noncontrast MRI could help differentiate G1 and G2/3 tumors, to make the clinical decision, and screen pNETs grade. 4 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:1124-1136.

Tumor-Infiltrating Neutrophils Predict Poor Survival of Non-Functional Pancreatic Neuroendocrine Tumor.

This study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). Tumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells. TINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set. Intratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

Hypoglycaemia associated with high grade transformation of a previously non-functioning pancreatic neuroendocrine tumour (pNET)

Hypoglycaemia associated with high grade transformation of a previously non-functioning pancreatic neuroendocrine tumour (pNET)

Long-term outcomes in MEN-1 patients with pancreatic neuroendocrine neoplasms: an Israeli specialist center experience.

The decreased life expectancy of MEN-1 patients is mainly related to pancreatic neuroendocrine tumors (pNETs). At best, limited data is available on the natural history of MEN-1-associated pNETs, as these tumors are rare and have a wide range of biologic behavior. Our study aims to explore the clinical course of patients with MEN-1-associated pNETs and the long-term outcomes. This longitudinal study was conducted on the MEN-1 cohort treated at our referral center over a 22-year period (1996-2018). Relevant clinical data were retrospectively analysed. Among the 33 MEN-1 patients included in our study, pNETs were identified in 21 subjects with a penetrance of 48% by the age of 50. Non-functioning and functioning pNETs were diagnosed in sixteen (76%) and five (24%) patients, respectively. Two-thirds of the patients had multifocal tumors. The median number of pancreatic macroscopic lesions per individual was 4.0 ± 3.9 (range 1-8) with a mean size of 1.3 ± 2.1 cm (range 0.5-10). The metastatic rate according to the dominant pNET lesion reached 100%, 62% and 6% for tumors sized > 4 cm, 2.1-4 cm, and 1-2 cm, respectively. Over the study period, one or more therapeutic interventions for pNETs were required in 20 out of the 21 patients. pNET-related metastatic complication was the main cause of death within this MEN-1 cohort. The overall survival rate for the pNETs patients was 86% during a mean follow-up period of 8.0 ± 4.6 years. In our MEN-1 cohort, non-functioning pNETs were the most frequent type of pancreaticoduodenal tumor, and the tumor size correlated with the risks of metastasis and death. Increased awareness, early diagnosis, and a multidisciplinary approach may improve the associated morbidity and mortality in these patients.