Nonfunctioning Neuroendocrine Tumors Research Articles

ГИГАНТСКАЯ НЕЙРОЭНДОКРИННАЯ ОПУХОЛЬ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ. КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ УСПЕШНОГО ИСПОЛЬЗОВАНИЯ ЛАПАРОСКОПИЧЕСКИХ ТЕХНОЛОГИЙ

Today, laparoscopic interventions on the abdominal organs cover an increasing range of application in both planned and emergency surgery. The case-study presents a clinical observation of the successful application of laparoscopic technology in a 59-year-old patient with a giant neuroendocrine tumor of the pancreas, admitted to hospital for emergency reasons with acute diagnosis of acute pancreatitis. Abdominal mass formation. According to the patient, she was not previously examined on an outpatient basis, was not observed by specialized specialists. In connection with the increase in pain and the lack of positive dynamics on the background of the ongoing conservative treatment after a full examination, the patient is served in the operating room for diagnostic laparoscopy, in which the picture of cystic neoplasm of the pancreatic tail. Performed laparoscopically assisted corporal coronary resection of the pancreas, drainage of the abdominal cavity.The histological conclusion: the wall of the cyst adjacent to the pancreatic tissue is represented by the growth of endocrine large cell carcinoma. The wall of the second cyst is represented by fibrous tissue with foci of hemorrhage and diffuse lymphocytic infiltration.Diagnosis of neuroendocrine tumors is based on the identification of a clinical picture due to hormonal dysfunctions; however, in patients with non-functioning neuroendocrine tumors, it is a difficult task to identify or suspect such a disease. The modern development of laparoscopic surgery after the period of mastering almost all types of surgical interventions has not exhausted its potential and requires improvement in new sections of surgery, including interventions on the pancreas in a first-aid hospital.

Ultrastructural comparative analysis of neuroendocrine tumors of pancreas

Detection of ultrastructural distinctions of tumor cells and cell-to-cell cooperation in insulinomas and nonfunctioning neuroendocrine tumors of pancreas. Ultrastructural study of 38 insulinomas and 35 nonfunctioning neuroendocrine tumors of pancreas of the patients treated at Vishnevskiy Surgery Institute from 2010 to 2015. Insulinomas are characterized by high differentiation of intracellular organelles and specific secretory granules. In insulinomas the number of immature endocrine granules exceeded the number of mature granules. The tumor cells were often joined together and held with desmosomes ensuring very tight connection. Desmosome complexes were characterized by their extended length. Such ultrastructural changes were not followed by destruction of tumor cells. There was formation of specific syncytium-like structures consisting of cells connected by cytoplasmic channels with the common cytoplasm with cell organelles. In nonfunctioning tumors the most of the granules were distinguished by polymorphism and had no specific ultrastructure indicating the synthesized hormone. In large areas there were loss of plasmolemma integrity, up to its complete absence, which led to unification of cytoplasmic contents of the cells. Common junctions dominated in nonfunctioning tumors. Desmosomes were rare, poorly developed, and in the form of immature and reduced junctions. Complex cellular junctions are well developed in the cells, ensuring tight connection of tumor cells, reducing their invasive and metastatic potential. Nonfunctioning neuroendocrine tumors on the contrary are characterized by underdevelopment of cellular organelles and immaturity of secretory granules. Predominance of weak direct cell junctions, rupture of membranes of neighboring cells with simultaneous reduction of desmosomes facilitate the migration of individual tumor cells and formation of metastases.

Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers.

Some biomarkers for functioning and non-functioning neuroendocrine neoplasms (NENs) are currently available. Despite their application in clinical practice, results should be interpreted cautiously. Considering the variable sensitivity and specificity of these parameters, there is an unmet need for novel biomarkers to improve diagnosis and predict patient outcome. Nowadays, several new biomarkers are being evaluated and may become future tools for the management of NENs. These biomarkers include (1) peptides and growth factors; (2) DNA and RNA markers based on genomics analysis, for example, the so-called NET test, which has been developed for analyzing gene transcripts in circulating blood; (3) circulating tumor/endothelial/progenitor cells or cell-free tumor DNA, which represent minimally invasive methods that would provide additional information for monitoring treatment response and (4) improved imaging techniques with novel radiolabeled somatostatin analogs or peptides. Below we summarize some future directions in the development of novel diagnostic and predictive/prognostic biomarkers in NENs. This review is focused on circulating and selected tissue markers.

Aptasensor for Quantifying Pancreatic Polypeptide

Herein, a simple colorimetric aptasensor based on unmodified gold nanoparticles (AuNPs) has been developed for quantifying pancreatic polypeptide (PP), a peptide hormone associated with nonfunctional neuroendocrine pancreatic tumor (NF-PNET). First, several PP-specific aptamers have been screened by systematic evolution of ligands by exponential enrichment. The generated aptamers showed specificity and affinity higher than those reported so far. The sensing platform was constructed based on the optical properties of AuNPs as well as the adsorption of single-stranded DNA aptamers. The high sensitivity of the developed aptasensor was achieved by optimizing the sensing conditions, including salt tolerance, time of reaction, and optimal aptamer concentration. The developed aptasensor showed a wide linear dynamic range (1–60 nM) with a limit of detection of 521 pM. Furthermore, the performance of the aptasensor was evaluated for the detection of PP in human serum and showed recovery values ranging between 92.4...

Everolimus for the treatment of advanced gastrointestinal or lung nonfunctional neuroendocrine tumors in East Asian patients: a subgroup analysis of the RADIANT-4 study.

BackgroundIn RADIANT-4, everolimus showed an improvement of 7.1 months in median progression-free survival (PFS) vs placebo among patients with advanced, well-differentiated, nonfunctional neuroendocrine tumors (NETs) of gastrointestinal (GI) or lung origin. The present analysis focuses on the effect of everolimus on the East Asian-subgroup population of the RADIANT-4 study.MethodsPatients were randomized to receive everolimus 10 mg/day or matching placebo. The primary end point was PFS (central review). Secondary end points were overall response rate, safety, and tolerability.ResultsAmong 302 patients enrolled in RADIANT-4, 46 were included in the East Asian subgroup (everolimus, n=28; placebo, n=18) analysis. Everolimus was associated with an 82% reduction in the relative risk of disease progression or death (HR 0.18, 95% CI 0.09–0.38). The median PFS (central review) in this subgroup was 11.2 months with everolimus vs 3.1 months with placebo. Adverse events (AEs) occurred in all 28 patients treated with everolimus and ten patients receiving placebo. The majority of these AEs were grade 1 or 2. Most commonly reported ($30% of incidence) drug-related AEs of any grade included stomatitis (75%, n=21) and rash (43%, n=12) in the everolimus arm.ConclusionEverolimus demonstrated a clinically meaningful PFS benefit in the East Asian population. The safety findings were consistent with the known safety profile of everolimus. These results support the use of everolimus in the East Asian population with advanced, nonfunctional NETs of GI or lung origin.

Prognostic factors in non-functional neuroendocrine tumors of the pancreas in a 70 patients series.

Background: The aim of this study was to analyze prognostic factors for survival and recurrence in patients with resected pancreatic non-functional neuroendocrine tumors (NF-pNETs). Methods: Medical records of 70 patients with resected NF-pNETs were retrospectively reviewed. The variables studied were: age, sex, form of presentation, (sporadic /familial tumors), type of tumor, localization, diagnostic tests (analytical/image tests), type of surgery, tumor size, multifocal tumors and recurrent rates. The new WHO classification (2010) was used. Results: There were 41 men and 29 women. Mean age was 42.7 years. Regarding the mode of presentation, it was sporadic in 51 patients (72,8%) and 19 cases were familial neuroendocrine tumors (27.2%) in association with MEN 1 syndrome. Distal pancreatectomy was the most common surgical procedure. There was synchronous liver metastasis in 28 patients, all of them from the sporadic group. According to the WHO classification, 19 patients had a NF-pNETs G1, 34 NF-pNETs G2 and 17 with a poorly-differentiated carcinoma. The 5-year survival in well-differentiate tumors was 94,7 %. In contrast very poorly-differentiate tumors global survival is less than 5 years. Survival and recurrence rates after a mean follow-up of 94,3 months were 69.8 % and 27 % respectively. Conclusion: In our experience, WHO classification was an independent prognostic factor in NF-pNETs survival.

Prognostic factors in non-functional neuroendocrine tumors of the pancreas in a 70 patients series.

Prognostic factors in non-functional neuroendocrine tumors of the pancreas in a 70 patients series.

Pancreatic non-functioning neuroendocrine tumor and lynch syndrome: aA new tumor association

Pancreatic non-functioning neuroendocrine tumor and lynch syndrome: aA new tumor association

Pancreatic non-functioning neuroendocrine tumor and ,lynch syndrome: a new tumor association

Background: Lynch Syndrome (LS) is a autosomal dominant inheritance caused by a mutation in one of the deoxyribonucleic acid mismatch repair genes. Mutations occur most frequently in the MLH1 and MSH2 genes, followed by MSH6 and then finally PMS2. Colorectal carcinoma (CRC) is the most commonly associated neoplasm. But other neoplasm had been associated: endometrium, gastric, ovarian, breast, small intestine, renal, skin, brain and pancreatic adenocarcinoma. However pancreatic neuroendocrine tumor (PNET), were suggested to be associated but with no confirmation to date. Methods: We present a 65 years old woman affected by LS. She had a CRC 20 year ago. Twelve years later had another one in the right colon. At age of 58 an endometrial cancer was resected. A genetic study was performed and discover a MLH1 MMR gene mutation. She had also a low grade ductal carcinoma of breast at the age of 63 with the same gene mutation. A gastroscopy found a duodenal adenocarcinoma. Results: A pancreaticoduodenectomy was performed. Histology reported a duodenal adenocarcinoma T1N0, two PNET, one G1 and another G2. IHC confirmed the lack of expression of MLH1 and PMS2 in all tumor except in the small PNET. Polymerase chain reaction showed instability only in CRC, duodenal and skin tumors. Conclusion: The association of pancreatic NE tumors and LS is now confirmed and its due to the mutation of the MLH1 and PMS2 nuclear proteins. A gastroscopy with duodenal study should be added in the follow-up of theses patients.

Early recurrence of well‐differentiated (G1) neuroendocrine liver metastasis after curative‐intent surgery: Risk factors and outcome

The objective of the current study was to identify the risk of early vs late recurrence of well-differentiated (G1) neuroendocrine liver metastasis (NELM) after curative-intent resection. Patients who underwent curative-intent resection for well-differentiated NELM were identified from a multi-institutional database. Clinicopathological details, as well as the long-term overall (OS) and recurrence free survival (RFS) were obtained and compared. The optimal cutoff value to differentiate early and late recurrence was determined to be 1 year based on trend curve analysis. Among the 548 patients undergoing curative resection for NELM, 162 patients had a well-differentiated NELM. After a median follow-up of 69 months, 59 (36.4%) patients had tumor recurrence; 23 (39.0%) patients recurred within 1 year (early recurrence) after surgery, while 36 (61.0%) recurred after 1 year (late recurrence). Early recurrence was associated with worse outcome vs late recurrence (5-year OS, 72.4% vs 92.0%; P = 0.020) and no recurrence (5-year OS, 72.4% vs 100.0%; P < 0.001). In addition, postrecurrence survival was worse within 36 months after recurrence among patients who recurred early compared with patients who recurred late (survival after recurrence at 36 months: early recurrence, 71.6% vs late recurrence, 91.4%; P = 0.047), although survival was comparable at 60 months (early recurrence, 71.6% vs late recurrence, 70.0%; P = 0.304). On multivariable analysis, nonfunctional neuroendocrine tumors (hazard ratio [HR], 4.4; 95% confidence interval [CI], 1.2-16.7; P = 0.029) and lymph node metastasis (HR, 3.6; 95% CI, 1.1-11.1; P = 0.028) were independent risk factors for early recurrence, whereas lymph node metastasis (HR, 3.0; 95% CI, 1.2-7.8; P = 0.020) and R1 resection (HR, 3.9; 95% CI, 1.4-10.5; P = 0.008) were independently associated with late recurrence. Roughly, one-third of patients with well-differentiated NELM experienced a recurrence following curative-intent surgery. Among patients who recurred, two out of five patients recurred within 1 year after surgery. Early recurrence of well-differentiated NELM was associated with the hormone functional status and lymph node metastasis.

Endoscopic ultrasound-guided radiofrequency ablation for management of benign solid pancreatic tumors

Background Radiofrequency ablation (RFA) has been increasingly employed in experimental and clinical settings for the management of pancreatic lesions. This study aimed to assess the safety and efficacy of endoscopic ultrasound (EUS)-guided RFA for benign solid pancreatic tumors. Methods In a single-center, prospective study, 10 patients with benign solid pancreatic tumors underwent EUS-RFA. After the RFA electrode had been inserted into the pancreatic mass, the radiofrequency generator was activated to deliver 50 W of ablation power. Results Among the 10 patients, 16 sessions of EUS-RFA were successfully performed. Diagnoses included nonfunctioning neuroendocrine tumor (n = 7), solid pseudopapillary neoplasm (n = 2), and insulinoma (n = 1); the median largest diameter of the tumors was 20 mm (range 8 – 28 mm). During follow-up (median 13 months), radiologic complete response was achieved in seven patients. Two adverse events (12.4 %; 1 moderate and 1 mild) occurred. Conclusions EUS-RFA may be a safe and potentially effective treatment option in selected patients with benign solid pancreatic tumors. Multiple sessions may be required if there is a remnant tumor, and adverse events must be carefully monitored.

Validation of American Joint Committee on Cancer (AJCC) 8th edition for pancreatic neuroendocrine tumor

Introduction: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic neuroendocrine tumor (NET) included several significant changes. This study aim to evaluate this staging system compared to the 7th edition AJCC staging system. Methods: Using Korean tumor registry system - Bilary pancreas (KOTUS-BP) and Korean Pancreas Surgery Club (KPSC) database (2000–2014), 486 patients who underwent surgery for nonfunctional neuroendocrine tumor of pancreas were identified. Except for 39 (8.0%) cases with grade 3 (G3), 447 patients with G1, G2 were included in this study. Overall survival and disease free survival were calculated using the Kaplan-Meier method and compared by log-rank tests. Results: Poor discrimination in 10 years overall survival rate was noted between stage III and IV. There was 10-year disease free survival discrimination by stage: I, 93.2%; II, 83.1%; III, 38.9%; IV, 0.0% (p < .0001). Significant difference in 10 years disease free survival rate existed according to T stage (T1 93.3% vs. T2 84.8% vs. T3 53.3% vs. T4 36.0%; p < 0.001) and grade (G1 91.9% vs. G2 39.4%; p < 0.001). There was significant difference in 10 years overall survival rate between N0 versus N1 (84.4% vs. 56.3%; p = 0.001). Conclusions: This is the first large-scale validation of the AJCC 8th edition staging system for pancreatic neuroendocrine tumor. The revised 8th system provides better discrimination compared to that of the 7th-edition system.

Ampullary neuroendocrine neoplasms: surgical experience of a rare and challenging entity

Ampullary neuroendocrine neoplasms (NENs) account for < 0.3% of gastrointestinal NENs. Surgical options include transduodenal ampullectomy/tumour excision or pancreaticoduodenectomy (PD). We report the experience of two high-volume pancreatic surgical centres of ampullary NENs. Clinical records of patients who underwent surgery for ampullary NENs (January 2007-November 2017) in the study centres were retrieved retrospectively. We evaluated clinical-pathological features, post-operative outcome and follow-up (FU). Eighteen patients (9 M/9 F, averaging 62years) were enrolled. All but one were non-functioning NENs; four (22%) patients presented with jaundice. Seven (39%) of the patients underwent ampullectomy/excision (median tumour size 1.5cm), and 11 (61%) patients underwent PD (median tumour size 2.4cm). The median operation time of ampullectomy/excision was 221min with operative blood loss of 75ml (vs. 506min and 425ml in PD). The median hospital stay was 10days in both groups. Overall surgical morbidity was 33%, due to four biochemical leaks, one pancreatic fistula and one abdominal haemorrhage. No reoperations were needed. The median tumour size was 1.8 (range 0.5-6.7)cm. All G2-G3 NENs were N1 (vs. 1/7 in G1 NENs). Three (17%) cases were mixed exocrine/G3 NECs. After a median FU of 45 (up to 124)months, recurrence occurred in four G3 NEC (31%) patients (median disease-free survival 14months) after an R0 PD. Disease-related survival was 93, 77 and 66% at 1, 3 and 5years, respectively. Ampullary NENs are mostly G1-G2 neoplasms. Lymph node metastases rarely occur in G1 NENs < 2cm in size, which may be treated with ampullectomy/excision. Survival is 66% 5years after surgery.

Abstract 1799: ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct “alpha-cell signature” subgroup

Abstract Pancreatic neuroendocrine tumors (PanNETs) or islet cell tumors are a rare neuroendocrine malignancy with an annual incidence of less than 1 per 100,000 per year. Current classification scheme for PanNETs include grade and stage. While well-differentiated PanNETs can be successfully treated with surgery, there are few treatments for metastatic PanNETs. A greater understanding of the cells of origin of PanNETs, tumor progression and pathway pathogenesis may guide the development of novel therapeutic options. The most commonly mutated genes in PanNETs are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing (n=33) and Illumina 450K DNA methylation (n=32) analysis on randomly selected PanNETs to reveal two distinct subgroups with one group consisting exclusively of A-D-M mutant PanNETs. Pair-wise correlation of gene expression between all PanNETs, showed A-D-M mutant PanNETs are more homogeneous as a group than A-D-M WT PanNETs. Among A-D-M mutant PanNETs, mutants with the same genotype (mutations in ATRX/DAXX/MEN1) did not show greater gene expression correlation. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature similar to that of alpha cells (pval &amp;lt; 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. We validated our subtype classification and A-D-M mutant panNET alpha signature using two independent PanNETs expression dataset. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells. Citation Format: Saurabh V. Laddha, Chang S. Chan, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy Chan, David S. Klimstra, David C. Allis, Laura H. Tang. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct “alpha-cell signature” subgroup [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1799.

Non-functional neuroendocrine pancreatic tumours: Experience of a surgical cohort in a tertiary centre

Non-functional neuroendocrine pancreatic tumours: Experience of a surgical cohort in a tertiary centre

The number of positive nodes accurately predicts recurrence after pancreaticoduodenectomy for nonfunctioning neuroendocrine neoplasms

The number of positive nodes accurately predicts recurrence after pancreaticoduodenectomy for nonfunctioning neuroendocrine neoplasms

The number of metastatic lymph nodes is an useful predictive factor of recurrence after surgery for non-metastatic nonfunctional neuroendocrine tumors of the pancreas

The number of metastatic lymph nodes is an useful predictive factor of recurrence after surgery for non-metastatic nonfunctional neuroendocrine tumors of the pancreas

Prognostic factors in nonfunctional well-differentiated gastroenteropancreatic neuroendocrine tumors: Single Institute Experience.

e16176Background: Grade 1 & 2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are well-differentiated (WD). Methods: We evaluated 115 nonfunctional WD GEP-NETs retrospectively. Results: Med...

Endoscopic ultrasound-guided radiofrequency ablation for management of benign solid pancreatic tumors.

Radiofrequency ablation (RFA) has been increasingly employed in experimental and clinical settings for the management of pancreatic lesions. This study aimed to assess the safety and efficacy of endoscopic ultrasound (EUS)-guided RFA for benign solid pancreatic tumors. In a single-center, prospective study, 10 patients with benign solid pancreatic tumors underwent EUS-RFA. After the RFA electrode had been inserted into the pancreatic mass, the radiofrequency generator was activated to deliver 50 W of ablation power. Among the 10 patients, 16 sessions of EUS-RFA were successfully performed. Diagnoses included nonfunctioning neuroendocrine tumor (n = 7), solid pseudopapillary neoplasm (n = 2), and insulinoma (n = 1); the median largest diameter of the tumors was 20 mm (range 8 - 28 mm). During follow-up (median 13 months), radiologic complete response was achieved in seven patients. Two adverse events (12.4 %; 1 moderate and 1 mild) occurred. EUS-RFA may be a safe and potentially effective treatment option in selected patients with benign solid pancreatic tumors. Multiple sessions may be required if there is a remnant tumor, and adverse events must be carefully monitored.

The number of positive nodes accurately predicts recurrence after pancreaticoduodenectomy for nonfunctioning neuroendocrine neoplasms

BackgroundThe most appropriate nodal staging for pancreatic neuroendocrine neoplasms (PanNENs) is unclear. Aim of the study was to evaluate the effect of the number of positive lymph nodes on prognosis after pancreaticoduodenectomy for PanNENs. MethodsA retrospective analysis of pancreaticoduodenectomies for nonfunctioning PanNENs was performed. PanNENs with nodal metastases (N+) were classified into N1 (1 to 3 positive lymph nodes) and N2 (4 or more positive lymph nodes). Univariate and multivariate analyses of disease-free survival were performed. Results157 patients were included. 99 patients (63%) had N0 PanNENs whereas 58 patients (37%) had nodal involvement (N+). Patients with N0 PanNENs had a 3-year disease-free survival rate of 89% compared with 83% and 75% in patients with N1 and N2 PanNENs, respectively (P < 0.0001). Independent predictors of disease-free survival were the presence of necrosis, lymph node ratio and nodal status. Factors positively correlated with the number of positive lymph nodes were the Ki67 value, the T stage and the number of examined lymph nodes. Similar percentage of N0 and N+ PanNENs was demonstrated for a cut-off of 13 examined lymph nodes. ConclusionsThe number of positive lymph nodes is accurate in predicting recurrence for PanNENs. Thirteen examined lymph nodes seems to be the minimum number of lymph nodes to be resected/examined in patients who undergo pancreaticoduodenectomy for PanNENs.