The Evolution of Surgical Strategies for Pancreatic Neuroendocrine Tumors (Pan-NENs): Time-trend and Outcome Analysis From 587 Consecutive Resections at a High-volume Institution.

OBJECTIVE: The objective of the present analysis is 2-fold: first, to define the evolution of time trends on the surgical approach to pancreatic neuroendocrine neoplasms (Pan-NENs); second, to perform a complete analysis of the predictors of oncologic outcome. BACKGROUND: Reflecting their rarity and heterogeneity, Pan-NENs represent a clinical dilemma. In particular, there is a scarcity of data regarding their long-term follow-up after surgical resection. METHODS: From the Institutional Pan-NEN database, 587 resected cases from 1990 to 2015 were extracted. The time span was arbitrarily divided into 3 discrete clusters enabling a balanced comparison between patient groups. Analyses for predictors of recurrence and survival were performed, together with conditional survival analyses. RESULTS: Among the 587 resected Pan-NENs, 75% were nonfunctioning tumors, and 5% were syndrome-associated tumors. The mean age was 54 years (±14 years), and 51% of the patients were female. The median tumor size was 20 mm (range 4 to 140), 62% were G1, 32% were G2, and 4% were G3 tumors. Time trends analysis revealed that the number of resected Pan-NENs constantly increased, while the size (from 25 to 20 mm) and G1 proportion (from 65% to 49%) decreased during the study period. After a mean follow-up of 75 months, recurrence analysis revealed that nonfunctioning tumors, tumor grade, N1 status, and vascular invasion were all independent predictors of recurrence. Regardless of size, G1 nonfunctioning tumors with no nodal involvement and vascular invasion had a negligible risk of recurrence at 5 years. CONCLUSIONS: Pan-NENs have been increasingly diagnosed and resected during the last 3 decades, revealing reliable predictors of outcome. Functioning and nodal status, tumor grade, and vascular invasion accurately predict survival and recurrence with resulting implications for patient follow-up.

Are Cystic Pancreatic Neuroendocrine Tumors an Indolent Entity Results from a Single-Center Surgical Series.

INTRODUCTION: Cystic pancreatic neuroendocrine tumors (CPanNETs) represent an uncommon variant of pancreatic neuroendocrine tumors (PanNETs). Due to their rarity, there is a lack of knowledge with regard to clinical features and postoperative outcome. METHODS: The prospectively maintained surgical database of a high-volume institution was queried, and 46 resected CPanNETs were detected from 1988 to 2015. Clinical, demographic, and pathological features and survival outcomes of CPanNETs were described and matched with a population of 92 solid PanNETs (SPanNETs) for comparison. RESULTS: CPanNETs accounted for 7.8% of the overall number of resected PanNETs (46/587). CPanNETs were mostly sporadic (n = 42, 91%) and nonfunctioning (39%). Two functioning CPanNETs were detected (4.3%), and they were 2 gastrinomas. The median tumor diameter was 30 mm (range 10-120). All tumors were well differentiated, with 38 (82.6%) G1 and 8 (17.4%) G2 tumors. Overall, no CPanNET showed a Ki-67 >5%. A correct preoperative diagnosis of a CPanNET was made in half of the cases. After a median follow-up of >70 months, the 5- and 10-year overall survival of resected CPanNETs was 93.8 and 62.5%, respectively, compared to 92.7 and 84.6% for SPanNETs (p > 0.05). The 5- and 10-year disease-free survival rates were 94.5 and 88.2% for CPanNETs and 81.8 and 78.9% for SPanNETs, respectively (p > 0.05). CONCLUSION: In the setting of a surgical cohort, CPanNETs are rare, nonfunctional, and well-differentiated neoplasms. After surgical resection, they share the excellent outcome of their well-differentiated solid counterparts for both survival and recurrence.

Corrigendum: Whole-genome landscape of pancreatic neuroendocrine tumours.

This corrects the article DOI: 10.1038/nature21063.

Comparison of imaging-based and pathological dimensions in pancreatic neuroendocrine tumors.

AIM: To establish the ability of magnetic resonance (MR) and computer tomography (CT) to predict pathologic dimensions of pancreatic neuroendocrine tumors (PanNET) in a caseload of a tertiary referral center. METHODS: Patients submitted to surgery for PanNET at the Surgical Unit of the Pancreas Institute with at least 1 preoperative imaging examination (MR or CT scan) from January 2005 to December 2015 were included and data retrospectively collected. Exclusion criteria were: multifocal lesions, genetic syndromes, microadenomas or mixed tumors, metastatic disease and neoadjuvant therapy. Bland-Altman (BA) and Mountain-Plot (MP) statistics were used to compare size measured by each modality with the pathology size. Passing-Bablok (PB) regression analysis was used to check the agreement between MR and CT. RESULTS: Our study population consisted of 292 patients. Seventy-nine (27.1%) were functioning PanNET. The mean biases were 0.17 ± 7.99 mm, 1 ± 8.51 mm and 0.23 ± 9 mm, 1.2 ± 9.8 mm for MR and CT, considering the overall population and the subgroup of non-functioning- PanNET, respectively. Limits of agreement (LOA) included the vast majority of observations, indicating a good agreement between imaging and pathology. The MP further confirmed this finding and showed that the two methods are unbiased with respect to each other. Considering ≤ 2 cm non-functioning-PanNET, no statistical significance was found in the size estimation rate of MR and CT (P = 0.433). PBR analysis did not reveal significant differences between MR, CT and pathology. CONCLUSION: MR and CT scan are accurate and interchangeable imaging techniques in predicting pathologic dimensions of PanNET.

Whole-genome landscape of pancreatic neuroendocrine tumours.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

Role of Combined 68Ga-DOTATOC and 18F-FDG Positron Emission Tomography/Computed Tomography in the Diagnostic Workup of Pancreas Neuroendocrine Tumors: Implications for Managing Surgical Decisions.

OBJECTIVES: Ga-DOTATOC (Ga) positron emission tomography (PET)/computed tomography (CT) is recommended in the workup of pancreas neuroendocrine tumors (PanNETs); evidence suggests that F-FDG (F) PET/CT can also provide prognostic information. Aims of this study were to assess the role of combined Ga- and F-PET/CT in the evaluation of grade (G) 1-2 PanNETs and to test the correlation between F-PET/CT positivity and tumor grade. METHODS: Preoperative Ga- and F-PET/CT of 35 patients with surgically resected G1-2 PanNETs were evaluated. For grading, the 2010 World Health Organization Classification was used; an ancillary analysis with Ki67 cutoffs at 5% to 20% was conducted. Correlation between F-PET/CT positivity (SUVmax > 3.5) and grade was assessed. RESULTS: Of 35 PanNETs, 28.6% and 71.4% were G1 and G2 as per World Health Organization. Ga-PET/CT showed high sensitivity (94.3%) in detecting G1-2 PanNETs. F-PET/CT was positive in 20% and 76% G1 and G2 tumors (P = 0.002). F-PET/CT identified G2 PanNETs with high positive predictive value (PPV, 90.5%). F-PET/CT correlated with tumor grade also in the ancillary analysis (P = 0.009). CONCLUSIONS: The high sensitivity of Ga-PET/CT in NET detection is known. The high PPV of F-PET/CT in the identification of G2 forms suggests its potential role in PanNETs prognostication and risk stratification.

Distal pancreatectomy associated with multivisceral resection: results from a single centre experience.

PURPOSE: Tumors arising in the body/tail of the pancreas tend to be diagnosed at a more advanced stage, with a lower rate of resectability compared to disease of the head. Distal pancreatectomy (DP) associated to multivisceral resections (MVR) can represent a surgical option for selected patients with advanced tumors. METHODS: We retrospectively analyzed data of patients who underwent DP associated with MVR at our Institution over a 9-year period, and compared them to standard DP. MVR was defined as resection of at least one additional organ or vascular structure because of neoplastic involvement. RESULTS: Out of 508 DP, in 59 cases MVR was performed. The absolute incidence of complications was comparable between the two groups (69.5 % in MVR arm vs. 57.2 % in control arm, p = 0.072) but more patients in the study group had a Clavien-Dindo class ≥3 (18.6 vs. 9.8 %, p = 0.04). A longer operative time (291 ± 91 vs. 227 ± 67, p < 0.001), an increased need for intraoperative transfusions (21.4 vs. 3.3 %, p < 0.001) and a slightly longer hospitalization (9 [7-16] days vs. 8 [7-10]; p < 0.001) were observed in the MVR group. In patients with ductal adenocarcinoma (n = 118), mortality was comparable between groups (p = 0.44) over a median follow up of 26 [16-41] months. In contrast, among patients with neuroendocrine neoplasms, mortality was higher in the study group (p = 0.002). CONCLUSION: Multivisceral resection for cancer of body and tail of the pancreas is feasible in selected cases, with an acceptable surgical complication rate compared to standard procedures and a favorable long-term survival in ductal cancer.

Is routine imaging necessary after pancreatic resection? An appraisal of postoperative ultrasonography for the detection of pancreatic fistula.

OBJECTIVES: This study aimed to assess whether routine transabdominal ultrasonography (US) is clinically helpful for the early detection of postoperative pancreatic fistula (PF). METHODS: In a prospective cohort of patients undergoing partial pancreatectomy, US was performed on postoperative day (POD) 3. Potential predictors of PF, including amylase value in drains (AVD) on POD 1, were investigated. A tree-based classification model of the independent predictors of PF was also performed. RESULTS: One hundred seventy-three patients were analyzed. A peripancreatic collection on US and an AVD 5000 U/L or greater on POD 1 were predictors of PF. In the tree-based classification model, patients were stratified by AVD on POD 1. For values less than 5000 U/L (incidence of PF, 11.3%), US had a sensitivity of 23.1% and a specificity of 97.5%. For AVD 5000 U/L or greater (incidence of PF, 70.7%), sensitivity was 46.3% and specificity was 100%. CONCLUSIONS: Despite the presence of a peripancreatic collection as a predictor of PF, US-as a diagnostic test-resulted to be highly specific but poorly sensitive even in the tree-based classification model. Therefore, its role does not seem to be clinically relevant and does not add value to AVD on POD 1, which remains the most powerful and relevant early predictor of PF.

Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling.

The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-ß, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.

Diabetes mellitus does not impact on clinically relevant pancreatic fistula after partial pancreatic resection for ductal adenocarcinoma.

BACKGROUND: The prevalence of diabetes mellitus (DM) in patients with pancreatic ductal adenocarcinoma (PDAC) ranges from 20 to 80%. In patients undergoing resection, it is unclear whether DM impacts on clinically relevant pancreatic fistula (CR-PF). METHODS: To address this issue, data from 602 consecutive partial pancreatic resections were analyzed using univariate and multivariate models. RESULTS: There were 120 patients with DM; 84 had longstanding DM and 36 a new-onset DM. The incidence of CR-PF was greater among nondiabetics (11.8% vs 5.0%; P = .043), who were also more likely to have a soft pancreatic texture (79.5% vs 46.0%; P = .001) or combined presence of soft texture and small pancreatic duct (high-risk pancreas; P = .001). All these variables did not differ when stratifying by DM type. Univariate analysis showed that gender (P = .005), body mass index (P = .05), DM (P = .043), pancreatic texture (P = .001), pancreatic duct size (P = .012), and the combined presence of soft parenchyma and small duct (P = .001) were associated with CR-PF. On multivariate analysis, DM resulted to be a negative predictor of CR-PF (odds ratio [OR], 0.53; P = .047). Additional variables associated with an increased probability of CR-PF formation were male gender (OR, 3.48; P = .002), soft pancreatic texture (OR, 2.19), pancreatic duct size <3 mm (OR, 1.79), and the combined presence of soft pancreas and small duct (OR, 2.24). CONCLUSION: DM is not a risk factor for CR-PF after resection of PDAC. The decreased incidence of CR-PF in diabetics is likely to be a consequence of a decreased frequency of high-risk features of the pancreatic gland (soft texture and/or small duct).

Perioperative management of patients undergoing pancreatic resection: implementation of a care plan in a tertiary-care center.

Evidence-based perioperative management is important for a successful outcome after pancreatic surgery. Use of protocolized pathways of care based on fast-track concepts has been shown to reduce hospital stay and contain costs. These regimens include pain control, early device removal (nasogastric tube, abdominal drains), enforced early mobilization, and early oral feeding. In this article, current evidence on perioperative management of pancreatic resections was analyzed in the attempt to implement our institutional care plan.