Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors Research Articles

Enucleation for Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors Larger than 2 Centimeters Is Associated with Equivalent Morbidity and Survival Compared to Smaller Tumors: A Multi-Institutional Study

Introduction: Nonfunctioning pancreatic neuroendocrine tumor (NF-PanNET) ≤2 cm can be observed or resected. Surgery remains recommended for NF-PanNET >2 cm but its extent, enucleation (EN) versus formal resection, remains controversial. Methods: Multicentric retrospective cohort of sporadic NF-PanNET patients treated with EN. Short- and long-term outcomes were compared according to tumor size on imaging ≤2 cm versus >2 cm. Results: 131 patients underwent EN for NF-PanNET, including 103 (79.0%) ≤2 cm and 28 (21.0%) >2 cm (extremes, 4–55 mm). Patients’ characteristics were comparable, and tumor characteristics only differed in their diameter. Clavien III-IV complications were similar (18.4% vs. 17.9%, p = 1.00) with one death in NF-PanNET ≤2 cm. Grade B/C pancreatic fistula were comparable (16.5% vs. 10.7%, p = 0.850). In NF-PanNET >2 cm there were more pT2/3 stage tumors (85.7% vs. 21.4%, p < 0.001), similar rates of grade G2/3 tumors (25% vs. 16.5%, p = 0.408) with a median Ki67 of 2 (interquartile range: 1–3), and of lymphovascular and perineural invasions. Lymph node picking was done in 46 (35.1%) patients, with a higher median number of harvested lymph nodes in NF-PanNET >2 cm (4 vs. 3, p = 0.01). All were pN0. R0 resection rate (78.6% vs. 82.5%, respectively; p = 0.670) was equivalent. Five-year overall (100% vs. 99%, p = 0.602) and 10-year disease-free (96% vs. 92%, respectively; p = 0.532) survivals were comparable. Conclusions: EN for selected NF-PanNET >2 cm carries equivalent morbidity, overall and disease-free survivals compared to those observed with NF-PanNET ≤2 cm.

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.

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?

Management of small asymptomatic nonfunctioning pancreatic neuroendocrine tumors: Limitations to apply guidelines into real life

BackgroundInternational guidelines suggest a watchful strategy for small nonfunctioning pancreatic neuroendocrine tumors. The aim of this study was to evaluate the management and indications for surgery in patients with asymptomatic nonfunctioning pancreatic neuroendocrine tumors ≤2 cm. MethodsPatients with asymptomatic, incidental, sporadic nonfunctioning pancreatic neuroendocrine tumors ≤2 cm without nodal or distant metastases were included (2012–2016). A comparison between active surveillance and surgery groups was performed. ResultsOf the 101 included patients, 72% underwent active surveillanc and 28% were surgically treated. Patients submitted to surgery were significantly younger (53 vs 60 years, P = .013), had a higher incidence of positive 18F-fluorodeoxyglucose positron emission tomography (18% vs 50%, P = .003), and a higher incidence of cytologically determined G2 tumor (0% vs 14%, P = .008). Conservatively managed patients had a significantly smaller tumor size (12 vs 16 mm, P = .0001). The main reasons determining surgical choice were as follows: patient’s preference (32%), positive 18F-fluorodeoxyglucose positron emission tomography (21.5%), main pancreatic duct dilation (17.5%), cytologically determined G2 tumor (14.5%), and young age (14.5%). At a median follow-up of 40 months, all of the 73 patients conservatively managed were alive, with no evidence of distant metastases and none underwent surgery. Only 5 patients had a tumor growth >20%. ConclusionOne-third of patients with asymptomatic small nonfunctioning pancreatic neuroendocrine tumors ≤2 cm underwent surgery. Patient’s preference, initial tumor size, and young age were the main determinants of surgical indication. Preoperative diagnostic workup, including 18F-fluorodeoxyglucose positron emission tomography and cytologic grading, seems to be poorly accurate in determining malignant features in these small lesions.

Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors.

Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs. Thirty-three tissue samples were analyzed: they included samples from sporadic (n=9), von Hippel-Lindau (VHL)-related (n=10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n=10) as well as normal islet cells (n=4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools. In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs. MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.

Natural history of small nonfunctioning pancreatic neuroendocrine tumors.

515 Background: Asymptomatic sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are rare disease but are diagnosed more frequently than before. The aim of this study was to evaluate the natural course of small NF-PNETs. Methods: We performed retrospective study of patients with suspected NF-PNETs from 1999 to 2015. Patients older than 18 years with NF-PNETs diagnosed either by pathology or other clinical evidences were included. Patients with clinical symptoms of hormonal hypersecretion, more than 20 mm in size, local invasion, nodal or distant metastasis, less than two follow-up imaging studies , and follow-up period of less than 6 months were excluded. Results: Small NF-PNETs in patients initially recommended surveillance (n = 69; mean age, 58.9 ± 11.1 yrs) were mainly located in the pancreatic head (n = 32, 46.4%) with mean mass size of 10.9 ± 3.1 mm. The average follow-up period was 52.2 ± 38.7 months. Tumor size changes during the follow-up period were as follows: increased (n = 9, 13.0%), sustained (n = 58, 84.1%), decreased (n = 2, 2.9%). The mean growth rate of increasing tumor was 0.9 ± 2.9 mm/year. Non-hypervascular tumors showed a tendency to increase in size compared to hypervascular tumor. (P = 0.04) Thirteen patients (18.8%) underwent surgery during the follow-up at average 32.9 ± 42.6 months later. According to the WHO 2010 grade classification, grade 1 was found in 18 patients, grade 2 in 1 patient, and grade 3 in 0 patient. The pathologic AJCC TNM stages of surgically resected tumors were Ia in 7 patients, Ib in 1 patient, IIa in 2 patient, IIb in 1 patients. Two patients (10.0%) received reoperation for recurred tumors at 34 and 50 months after surgery. Two patients (2.9%) showed distant metastasis after surgery but no disease-related death occurred. Conclusions: Most of small NF-PNETs do not increase in the size and seldom show metastasis during follow-up. Wait-and-see strategy can be applied for NF-PNETs less than 2cm in size.

Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype

Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel-Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in tumors of the same stage and grade. The authors analyzed genotype-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype. Thirty-two samples were included for genome-wide mRNA gene expression analysis (9 VHL-associated, 10 MEN1-associated, and 9 sporadic NFPanNETs and 4 purified normal islet cell [NIC] samples). Validation of genes was performed by real-time polymerase chain reaction analysis and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype, and pathway analysis was curated. Consensus clustering of mRNA expression revealed separate clustering of NICs, VHL-associated NFPanNETs, and MEN1-associated NFPanNETs; whereas some sporadic tumors clustered with MEN1. Four of 5 MEN1-like sporadic PanNET subtypes had loss of heterozygosity at the MEN1 gene locus. Pathway analysis demonstrated subtype-specific pathway activation, comprising angiogenesis and immune response in VHL; neuronal development in MEN1; protein ubiquitination in the new MEN1/sporadic subtype; and cytokinesis and cilium/microtubule development in sporadic NFPanNETs. Among many genes, platelet-derived growth factor receptor β (PDGFRB), lymphoid enhancer-binding factor-1 (Lef-1), cyclin-dependent kinase 4 (CDK4), and CDK6 were upregulated in VHL or MEN1 NFPanNETs, providing potential subtype-specific treatment targets. Distinct mRNA expression patterns were identified in sporadic-associated, VHL-associated, and MEN1-associated NFPanNETs. The current results uncover new pathways involved in NFPanNETs that are subtype-specific and provide potential new diagnostic or therapeutic targets based on tumor subtype. Cancer 2018;124:636-47. © 2017 American Cancer Society.

MicroRNA and Gene Expression Profiling in Syndromic and Sporadic Non-Functioning Pancreatic Neuroendocrine Tumors: An Integrated Analysis

MicroRNA and Gene Expression Profiling in Syndromic and Sporadic Non-Functioning Pancreatic Neuroendocrine Tumors: An Integrated Analysis

Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: A French multicenter study

Nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are often discovered at a small size. No clear consensus exists on the management of NF-PNETs ≤ 2 cm. The aim of our study was to determine the prognostic value of indicators of malignancy in sporadic NF-PNETs ≤ 2 cm. Eighty patients were evaluated retrospectively in 7 French University Hospital Centers. Patients were managed by operative resection (operative group [OG]) or observational follow-up (non-OG [NOG]). Pathologic characteristics and outcomes were analyzed. Sixty-six patients (58% women) were in the OG (mean age, 59 years; 95% CI, 56.0-62.3; mean tumor size, 1.6 cm; 95% CI, 1.5-1.7); 14 (72% women, n = 10) were in the NOG (mean age, 63 years; 95% CI, 56-70; mean tumor size, 1.4 cm; 95% CI, 1.0-1.7). All PNETs were ranked using the European Neuroendocrine Tumor Society grading system. Fifteen patients (19%) had malignant tumors defined by node or liver metastasis (synchronous or metachronous). The median disease-free survival was different between malignant and nonmalignant PNETs, respectively: 16 (range, 4-72) versus 30 months (range, 1-156; P = .03). On a receiver operating characteristic (ROC) curve, tumor size had a significant impact on malignancy (area under the curve [AUC], 0.75; P = .03), but not Ki-67 (AUC, 0.59; P = .31). A tumor size cutoff was found on the ROC curve at 1.7 cm (odd ratio, 10.8; 95% CI; 2.2-53.2; P = .003) with a sensitivity of 92% and a specificity of 75% to predict malignancy. Based on our retrospective study, the cutoff of 2 cm of malignancy used for small NF-PNETs could be decreased to 1.7 cm to select patients more accurately.

Clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors.

To present our experiences in studying the clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs). The subjects included 9 patients with NF-pNETs who underwent pancreatectomy between April 1996 and September 2012. The surgical procedure, histopathological findings, and prognosis were assessed. All tumors were incidentally detected by computed tomography. The median diameter was 10 mm (5-32 mm). One patient was diagnosed with von Hippel-Lindau disease, and the others were sporadic cases. For the histopathological findings, 7 patients were G1; 1 patient was G2; and 1 patient, whose tumor was 22 mm, had neuroendocrine carcinoma (NEC). One patient who had a tumor that was 32 mm had direct invasion to a regional lymph node and 1 patient with NEC, had regional lymph node metastases. Six of the 7 patients with sporadic NF-pNETs, excluding the patient with NEC, had tumors that were smaller than 10 mm. Tumors smaller than 10 mm showed no malignancy and lacked lymph node metastasis. Sporadic NF-pNETs smaller than 10 mm tend to have less malignant potential. These findings suggest that lymphadenectomy may be omitted for small NF-pNETs after further investigation.

Long-term follow-up of resected small (< 2 cm) asymptomatic sporadic non-functioning pancreatic neuroendocrine tumors: Correlation between type of resection, histopathologic features, and outcome.

Long-term follow-up of resected small (< 2 cm) asymptomatic sporadic non-functioning pancreatic neuroendocrine tumors: Correlation between type of resection, histopathologic features, and outcome.

Sporadic nonfunctioning pancreatic neuroendocrine tumors: Prognostic significance of incidental diagnosis

Sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed as incidentalomas, and their resection is usually recommended. The prognostic significance of this diagnosis feature is poorly studied, and management of these tumors remains controversial. Clinical, pathologic characteristics and outcome of resected incidentally diagnosed NF-PNET (Inc) were compared with resected symptomatic NF-PNET (Symp) to better assess their biologic behavior and tailor their management. From 1994 to 2010, 108 patients underwent resection for sporadic nonmetastatic NF-PNET. Diagnosis was considered as incidental in patients with no abdominal symptoms or symptoms unlikely to be related to tumor mass. Patients with Inc were compared with patients with Symp, regarding demographics, postoperative course, pathology, and disease-free survival (DFS). Of the 108 patients, 65 (61%) had incidentally diagnosed tumors. Pancreas-sparing pancreatectomies (enucleation/central pancreatectomy) were performed more frequently in Inc (62%vs30%, P = .001). Inc tumors were more frequently <20 mm (65% vs 42%, P = .019), staged T1 (62% vs 33%, P = .0001), node negative (85% vs 60%; P = .005), and grade 1 (66% vs 33%, P = .0001). One postoperative death occurred in the Inc group, and postoperative morbidity was similar between the two groups (60% vs 65%, P = .59). DFS was substantially better in the Inc group (5-yearDFS = 92% vs 82%, P = .0016). Incidentally diagnosed NF-PNETs are associated with less aggressive features compared with symptomatic lesions but cannot always be considered to be benign. Operative resection remains recommended for most. Incidentally diagnosed NF-PNET may be good candidates for pancreas-sparing pancreatectomies.

Clinical Characteristics of Pancreatic Neuroendocrine Tumors in Japanese Patients With von Hippel-Lindau Disease

The aim of this study was to elucidate the clinical characteristics of pancreatic neuroendocrine tumors (NET) in Japanese patients with von Hippel-Lindau (VHL) disease. We sent a questionnaire to all members of the Japan Pancreas Society in 2002 asking for the number of patients with VHL and complications of NET and/or cystic lesion in the pancreas. Furthermore, we sent a second questionnaire to obtain detailed information about the clinical characteristics of pancreatic NET. A total of 58 patients with VHL were reported. Among these, 34 (59%) patients had pancreatic lesions, including 10 with pancreatic NET, 23 with a cystic lesion, and one with both. The mean age at identification of pancreatic NET was 34.6 years (range, 22-64 years). The mean diameter of the tumors was 4.3 cm (range, 1-12.5 cm). Distant metastases were found in 2 (20%) cases. During the follow-up period (3.3 years; range, 0-8 years), 7 patients are alive, and 2 patients died of hemangioblastomas. Pancreatic NET in the VHL disease showed a relatively lower incidence of metastasis compared with sporadic non-functioning pancreatic NET, yielding a favorable prognosis. Because they present no hormonal syndrome, periodic screening examinations are warranted to identify pancreatic NET at an early stage.