Prognosis of sporadic resected small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors - a multi-institutional study.

BACKGROUND: Malignant potential of small (≤20 mm) nonfunctional pancreatic neuroendocrine tumors (sNF-PNET) is difficult to predict and management remain controversial. The aim of this study was to assess the prognosis of sporadic nonmetastatic sNF-PNETs. METHODS: Patients were identified from databases of 16 centers. Outcomes and risk factors for recurrence were identified by uni- and multivariate analyses. RESULTS: sNF-PNET was resected in 210 patients, and 66% (n = 138) were asymptomatic. Median age was 60 years, median tumor size was 15 mm, parenchyma-sparing surgery was performed in 42%. Postoperative mortality was 0.5% (n = 1), severe morbidity rate was 14.3% (n = 30), and 14 of 132 patients (10.6%) with harvested lymph nodes had metastatic lymph nodes. Tumor size, presence of biliary or pancreatic duct dilatation, and WHO grade 2-3 were independently associated with recurrence. Patients with tumors sized ≤10 mm were disease free at last follow-up. The 1-, 3- and 5-year disease-free survival rates for patients with tumors sized 11-20 mm on preoperative imaging were 95.1%, 91.0%, and 87.3%, respectively. CONCLUSIONS: In sNF-PNETs, the presence of biliary or pancreatic duct dilatation or WHO grade 2-3 advocate for surgical treatment. In the remaining patients, a wait-and-see policy might be considered.

Smoking, alcohol and family history of cancer as risk factors for small intestinal neuroendocrine tumors: a systematic review and meta-analysis.

OBJECTIVES: Risk factors for small intestinal neuroendocrine tumors (SI-NETs) are not well understood. The aim of this systematic literature review was to identify risk factors for SI-NET and to further assess these by meta-analysis. MATERIAL AND METHODS: PubMed and abstracts from the ENETS and NANETS were searched for studies published until May 2015. Eligible studies were selected according to the PRISMA statement. RESULTS: Seven studies evaluating six individual populations were included (study accrual period 1980-2012) in the meta-analysis, involving 765 (range 17-325) cases and 502,282 (range 52-498,376) controls. All studies were case-control by design. The following risk factors were reported in ≥2 studies: family history of any cancer, family history of colorectal cancer, ever alcohol use and ever smoking. The pooled OR was 1.34 (95% CI: 1.12-1.60; p < .01; I2 = 0.0%) for family history of any cancer, 1.43 (95% CI: 1.15-1.79; p < .01; I2 = 0.0%) for family history of colorectal cancer, 1.04 (95% CI: 0.63-1.72; p = .87; I2 = 65.0%) for ever alcohol use and 1.40 (95% CI: 1.06-1.86; p < .05; I2 = 49.3%) for ever smoking. CONCLUSIONS: Family history of any cancer, family history of colorectal cancer and history of ever smoking were associated with an increased risk of SI-NET by meta-analysis. Alcohol consumption was not a significant risk factor for SI-NET. However, the studies reporting smoking and alcohol had a high degree of heterogeneity. Therefore, further studies are needed for clarification of smoking and alcohol as risk factors for the occurrence of SI-NET.

Role of laparoscopic enucleation in the treatment of pancreatic lesions: case series and case-matched analysis.

BACKGROUND: Previous studies report successful application of laparoscopic pancreatic enucleation (LPE). However, the evidence is limited to small series. This study aimed to evaluate the indications, technique and outcome of LPE at a tertiary care institution. METHODS: Between February 1998 and April 2016, 45 consecutive LPEs were performed at Oslo University Hospital-Rikshospitalet. Twenty-four (53.3 %) patients subjected to right-sided LPE (RLPE) were compared with 21 (46.7 %) patients who had undergone left-sided LPE (LLPE). A case-matched analysis (1:2) was performed to compare the outcomes following LLPE and laparoscopic distal pancreatectomy (LDP). RESULTS: Patient demographics, BMI, ASA score and pathological characteristics were similar between the RLPE and LLPE groups. Operative time was slightly longer for RLPE [123 (53-320) vs 102 (50-373) min, P = 0.09]. The rates of severe morbidity (≥Accordion grade III) and clinically relevant pancreatic fistula (grades B/C) were comparable, although with a trend for higher rate of complications following LLPE (16.7 vs 33.3 %; P = 0.19 and 20.8 vs 33.3 %, P = 0.34, respectively). The hospital stay was similar between RLPE and LLPE [5 (2-80) vs 7 (2-52), P = 0.49]. A case-matched analysis demonstrated shorter operating time [145 (90-350) vs 103 (50-233) min, P = 0.02], but higher readmission rate following LLPE (25 vs 3.1 %, P = 0.037). CONCLUSION: LLPE seems to be associated with a higher risk of postoperative morbidity and readmission rates than LDP. RLPE is a feasible, safe approach and a reasonable alternative to pancreatoduodenectomy in selected patients with pancreatic lesions.

Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma: A Nordic Multicenter Comparative Study.

BACKGROUND: This study aimed to evaluate the role of surgery for patients with high-grade pancreatic neuroendocrine carcinoma (hgPNEC) in a large Nordic multicenter cohort study. Prior studies evaluating the role of surgery for patients with hgPNEC are limited, and the benefit of the surgery is uncertain. METHODS: Data from patients with a diagnosis of hgPNEC determined between 1998 and 2012 were retrospectively registered at 10 Nordic university hospitals. Kaplan-Meier curves were used to compare the overall survival of different treatment groups, and Cox-regression analysis was used to evaluate factors potentially influencing survival. RESULTS: The study registered 119 patients. The median survival period from the time of metastasis was 23 months for patients undergoing initial resection of localized nonmetastatic disease and chemotherapy at the time of recurrence (n = 14), 29 months for patients undergoing resection of the primary tumor and resection/radiofrequency ablation of synchronous metastatic liver disease (n = 12), and 13 months for patients with synchronous metastatic disease given systemic chemotherapy alone (n = 78). The 3-year survival rate after surgery of the primary tumor and metastatic disease was 69 %. Resection of the primary tumor was an independent factor for improved survival after occurrence of metastatic disease. CONCLUSIONS: Patients with resected localized nonmetastatic hgPNEC and later metastatic disease seemed to benefit from initial resection of the primary tumor. Patients selected for resection of the primary tumor and synchronous liver metastases had a high 3-year survival rate. Selected patients with both localized hgPNEC and metastatic hgPNEC should be considered for radical surgical treatment.

A critical appraisal of transanal minimally invasive surgery (TAMIS) in the treatment of rectal adenoma: a 4-year experience with 51 cases.

OBJECTIVE: The aim of this study was to describe feasibility, postoperative morbidity, and histological outcome of transanal minimally-invasive surgery (TAMIS) in patients with rectal adenoma. MATERIAL AND METHODS: All patients who underwent TAMIS at a single institution from December 2011 to December 2015 were retrospectively included in the study. Feasibility was based on tumor size, distance of tumor from the anal verge, operative time, and hospital stay. Thirty-day morbidity was defined by the revised Accordion Classification system. Histological outcome included microscopic resection margin status, specimen fragmentation status, and grading of dysplasia in rectal adenoma. RESULTS: A total of 51 patients with rectal adenoma underwent TAMIS. The median tumor diameter was 32 (4-60) mm and the median distance from the anal verge 8 (3-14) cm. Median operative time was 40 (13-116) min and median length of hospital stay was 1 (0-25) days. Overall morbidity was 12% (four grade 1, one grade 2, and one grade 3 complications). 22% had a positive resection margin, whereas 31% had an indefinable resection margin status mostly due to tissue fragmentation. Median follow-up time was 7 (0-40) months. CONCLUSIONS: TAMIS is a challenging surgical technique for treatment of rectal adenoma. Our initial experience among 51 patients resulted in a high proportion of positive resection margins and a high fragmentation rate. The role of TAMIS in the treatment of rectal adenoma is to be defined through comparative studies.

Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape.

Pancreatic neuroendocrine neoplasms (PNENs) are rare, accounting for less than 5% of all pancreatic tumors. High-grade pancreatic neuroendocrine carcinomas (hgPNECs) represent about 5% of all PNENs. They show highly aggressive behavior with dismal prognosis. Throughout the last two decades, there has been a notable progress in basic and clinical research of PNENs and a therapeutic trend towards both more aggressive and minimally invasive surgery. Despite these advances, hgPNECs as a distinct clinical entity remains largely unexplored among surgeons. This review of current development in pathology reporting and surgical treatment of hgPNECs aims at increasing the awareness of an evolving field in pancreatic surgery.

Laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: results of a multicenter cohort study on 196 patients.

BACKGROUND: Laparoscopy is widely accepted as a feasible option for distal pancreatectomy. However, the experience in laparoscopic distal pancreatectomy (LDP) for pancreatic ductal adenocarcinoma (PDAC) is limited to a small number of studies, reported by expert centers. The present study aimed to evaluate perioperative and oncological outcomes after LDP for PDAC in a large, multicenter cohort of patients. METHODS: A retrospective analysis of the data on 196 patients with histologically verified PDAC, operated at Oslo University Hospital-Rikshospitalet (Oslo, Norway), Asan Medical Center (Seoul, Republic of Korea), Institut Mutualiste Montsouris (Paris, France) and University Hospital Southampton (Southampton, UK) between January 2002 and April 2015 was conducted. The patients with standard (SLDP) and extended (i.e., en bloc with adjacent organ, ELDP) resections were compared in terms of perioperative and oncological outcomes. RESULTS: Out of 196 LDP procedures, 191 (97.4 %) were completed through laparoscopy, while five (2.6 %) were converted to open surgery. ELDP was performed in 30 (15.7 %) cases. Sixty-one (31.9 %) patients experienced postoperative complications, including 48 (25.1 %) with pancreatic fistula. The rate of clinically relevant fistula (grade B/C) was 15.7 %. Median postoperative hospital stay was 8 (2-63) days. Median follow-up was 16 months. Median survival was 31.3 months (95 % CI 22.9-39.6). Three- and 5-year actuarial survival rates were 42.4 and 30 %, respectively. SLDP was associated with significantly higher survival compared with ELDP (p = 0.032). CONCLUSIONS: LDP seems to be a feasible and safe procedure, providing satisfactory oncological outcomes in patients with PDAC.

Diabetes, smoking, alcohol use, and family history of cancer as risk factors for pancreatic neuroendocrine tumors: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Risk factors for pancreatic neuroendocrine tumors (PNETs) are not well understood. The aim of this systematic review was to assess if diabetes mellitus, smoking, alcohol use, and family history of cancer are risk factors for PNETs. METHODS: MEDLINE and abstracts from the European and North American Neuroendocrine Tumor Societies (ENETS and NANETS) were searched for studies published until October 2013. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Five studies evaluating 4 individual populations were included (study accrual period 2000-2011) into the meta-analysis, involving 827 cases (range 160-309 per study) and 2,407 controls (range 233-924 per study). All studies had a case-control design and described regional series. The pooled adjusted odds ratio was 2.74 (95% CI: 1.63-4.62; p < 0.01; I(2) = 60.4%) for history of diabetes, 1.21 (95% CI: 0.92-1.58; p = 0.18; I(2) = 45.8%) for ever smoking, 1.37 (95% CI: 0.99-1.91; p = 0.06; I(2) = 0.0%) for heavy smoking, 1.09 (95% CI: 0.64-1.85; p = 0.75; I(2) = 85.2%) for ever alcohol use, 2.72 (95% CI: 1.25-5.91; p = 0.01; I(2) = 57.8%) for heavy alcohol use, and 2.16 (95% CI: 1.64-2.85; p < 0.01; I(2) = 0.0%) for first-degree family history of cancer. CONCLUSIONS: Diabetes mellitus and first-degree family history of cancer are associated with an increased risk of sporadic PNET. There was also a trend for diagnosis of sporadic PNET associated with heavy smoking. Alcohol use may be a risk factor for PNET, but there was considerable heterogeneity in the meta-analysis. These results suggest the need for a larger, homogeneous, international study for the clarification of risk factors for the occurrence of PNET.

Respiratory gated and prolonged acquisition 18F-FDG PET improve preoperative assessment of colorectal liver metastases.

BACKGROUND: Detection of small liver metastases from colorectal cancer by 18F-FDG PET/CT is hampered by high physiologic uptake in the liver parenchyma and respiratory movements during image acquisition. PURPOSE: To investigate whether two tailored 18F-FDG PET liver acquisitions (prolonged liver acquisition time [PL-PET] and repeated breath-hold respiratory gated liver acquisition [RGL-PET]) would improve detection of colorectal liver metastases, when added to a standard whole body PET (WB-PET). MATERIAL AND METHODS: Twenty consecutive patients referred to our hospital for surgical treatment of colorectal liver metastases diagnosed with contrast-enhanced CT underwent preoperative 18F-FDG PET/CT tailored for detection of liver metastases. Concordance between preoperative imaging results and true findings (histology and/or follow-up imaging) as well as changes in clinical management, based on 18F-FDG PET/CT findings, were documented. Background noise, defined as the standard deviation measured in a reference region within the normal liver parenchyma, was compared between the three 18F-FDG PET/CT protocols. RESULTS: WB-PET, PL-PET, and RGL-PET showed suspicious liver lesions in 18 out of 20 patients. Compared to WB-PET alone, the combination of PL-PET and RGL-PET showed additional lesions in the liver in seven out of the 18 patients. The combination of all three PET acquisitions changed clinical management in four patients. Two patients with negative PET results were later found to have benign liver lesions. CONCLUSION: The addition of tailored liver-specific 18F-FDG PET/CT protocols (PL-PET and RGL-PET) to a WB-PET, improved the detection of intrahepatic colorectal metastases, compared to WB-PET alone. Such add-ons can change clinical patient management of potentially resectable colorectal liver metastases.

Long-term outcome of laparoscopic surgery for pancreatic neuroendocrine tumors.

BACKGROUND: As most pancreatic neuroendocrine tumors (PNET) are relatively small and solitary, they may be considered well suited for removal by a minimally invasive approach. There are few large series that describe laparoscopic surgery for PNET. The primary aim of this study was to describe the feasibility, outcome, and histopathology associated with laparoscopic pancreatic surgery (LS) of PNET in a large series. METHODS: All patients with PNET who underwent LS at a single hospital from March 1997 to April 2011 were included retrospectively in the study. RESULTS: A total of 72 patients with PNET underwent 75 laparoscopic procedures, out of which 65 were laparoscopic resections or enucleations. The median operative time of all patients who underwent resections or enucleations was 175 (60-520) min, the median blood loss was 300 (5-2700) ml, and the median length of hospital stay was 7 (2-27) days. The overall morbidity rate was 42%, with a surgical morbidity rate of 21% and postoperative pancreatic fistula (POPF) formation in 21%. Laparoscopic enucleations were associated with a higher rate of POPF than were laparoscopic resections. Five-year disease-specific survival rate was 90%. The T stage, R stage, and a Ki-67 cutoff value of 5% significantly predicted 5-year survival. CONCLUSION: LS of PNET is feasible with acceptable morbidity and a good overall disease-specific long-term prognosis.

Single-incision versus conventional laparoscopic distal pancreatectomy: a single-institution case-control study.

PURPOSE: Laparoscopic distal pancreatectomy is becoming increasingly established at specialized surgical institutions worldwide. The purpose of this study was to compare single-incision laparoscopic distal pancreatectomy (panLESS) with conventional laparoscopic distal pancreatectomy (panLAP) to assess feasibility and 30-day morbidity. METHODS: Eight consecutive patients who underwent panLESS were matched with patients who underwent panLAP in the same time period. Matching criteria were age, body mass index, and American Society of Anesthesiologists score. Feasibility was based on tumor size, operative time, intraoperative bleeding, resection status, and hospital stay. Thirty-day morbidity was defined by the revised Accordion Classification system and the International Study Group on Pancreatic Fistula definition. RESULTS: Over a 19-month period, 8 and 16 patients were identified for panLESS and panLAP, respectively. There were no significant differences in tumor size, operative time, intraoperative bleeding, resection status, and hospital stay between the two groups. Surgical complications developed in four panLESS patients and five panLAP patients, and out of which, two patients from each group developed a postoperative pancreatic fistula (grade B). CONCLUSIONS: This study indicates that panLESS is comparable to panLAP in terms of feasibility. More experience is needed to define what role single-incision distal pancreatectomy should have in minimal invasive pancreatic surgery.

Surgical treatment of sporadic pancreatic neuroendocrine tumors: a state of the art review.

Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms. They are clinically diverse and divided into functioning and nonfunctioning disease, depending on their ability to produce symptoms due to hormone production. Surgical resection is the only curative treatment and remains the cornerstone therapy for this patient group, even in patients with advanced disease. Over the last decade there has been a noticeable trend towards more aggressive surgery as well as more minimally invasive surgery in patients with PNETs. This has resulted in improved long-term survival in patients with locally advanced and metastatic disease treated aggressively, as well as shorter hospital stays and comparable long-term outcomes in patients with limited disease treated minimally invasively. There are still controversies related to issues of surgical treatment of PNETs, such as to what extent enucleation, lymph node sampling, and vascular reconstruction are beneficial for the oncologic outcome. Histopathologic tumor classification is of high clinical importance for treatment planning and prognostic evaluation of patients with PNETs. A constant challenge, which relates to the treatment of PNETs, is the lack of an internationally accepted histopathological classification system. This paper reviews current issues on the surgical treatment of sporadic PNETs with specific focus on surgical approaches and tumor classification.

Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours.

PURPOSE: Somatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3-5. METHODS: Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative (68)Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV(max) and SUV(mean)) were used for PET/CT. RESULTS: The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV(max) on the PET/CT (p < 0.001; p < 0.05) and the IRS for SSTR2A with the SUV(mean) (p < 0.013). The level of SSTR2A score correlated significantly with chromogranin A staining and indirectly to the tumour grading. CONCLUSION: The highly significant correlation between SSTR2A and SSTR5 and the SUV(max) on the (68)Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of (68)Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using (68)Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy.

Portal vein reconstruction using primary anastomosis or venous interposition allograft in pancreatic surgery.

OBJECTIVE: Superior mesenteric vein/portal vein (SMV/PV) resection and reconstruction during pancreatic surgery are increasingly common. Several reconstruction techniques exist. The aim of this study was to evaluate characteristics of patients and clinical outcomes for SMV/PV reconstruction using interposed cold-stored cadaveric venous allograft (AG+) or primary end-to-end anastomosis (AG-) after segmental vein resections during pancreatic surgery. METHODS: All patients undergoing pancreatic surgery with SMV/PV resection and reconstruction from 2006 to 2015 were identified. Clinical and histopathologic outcomes as well as preoperative and postoperative radiologic findings were assessed. RESULTS: A total of 171 patients were identified. The study included 42 and 71 patients reconstructed with AG+ and AG-, respectively. Patients in the AG+ group had longer mean operative time (506 minutes [standard deviation, 83 minutes] for AG+ vs 420 minutes [standard deviation, 91 minutes] for AG-; P < .01) and more intraoperative bleeding (median, 1000 mL [interquartile range (IQR), 650-2200 mL] for AG+ vs 600 mL [IQR, 300-1000 mL] for AG-; P < .01). Neoadjuvant therapy was administered more frequently for patients in the AG+ group (23.8% vs 8.5%; P = .02). Patients with AG+ had a longer length of tumor-vein involvement (median, 2.4 cm [IQR, 1.6-3.0 cm] for AG+ vs 1.8 cm [IQR, 1.2-2.4 cm] for AG-; P = .01), and a higher number of patients had a tumor-vein interface >180 degrees (35.7% for AG+ vs 21.1% for AG-; P = .02). There was no difference in number of patients with major complications (42.9% for AG+ vs 36.6% for AG-; P = .51) or early failure at the reconstruction site (9.5% for AG+ vs 8.5% for AG-; P = 1). A subgroup analysis of 10 patients in the AG+ group revealed the presence of donor-specific antibodies in all patients. CONCLUSIONS: The short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts is comparable to that of reconstruction with primary end-to-end anastomosis. Graft rejection could be a contributing factor to severe stenosis in patients reconstructed with allograft.

Risk and protective factors for the occurrence of sporadic pancreatic endocrine neoplasms.

Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare, and of the few institutions that have published potential risk factors, findings have been heterogeneous. Our objective was to investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. The following results were obtained: In 201 cases and 603 controls, non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. Our study concluded that non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence.

Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas.

Fusion transcripts arising from the combination of exons residing on neighboring genes on the same chromosome may give rise to chimeric or novel proteins. Such read-through transcripts have been detected in different cancers where they may be of pathogenetic interest. In this study, we describe for the first time the expression of a read-through transcript in insulinomas, a functioning neuroendocrine pancreatic neoplasm. The read-through transcript INS-IGF2, composed of exons from the two genes proinsulin precursor (INS) and insulin­like growth factor 2 (IGF2), both mapping to chromosomal subband 11p15.5, was highly expressed in the two insulinomas analyzed. More precisely, version 2 of the INS-IGF2 transcript was expressed, indicating possible expression of the chimeric INS-IGF2 protein. We further identified a novel splice variant of the INS-IGF2 read-through transcript in one of the insulinomas, composed of exon 1 of INS3 and exons of IGF2. In the same tumor, we found high expression of INS3 and the presence of the A allele at SNP rs689. SNP rs689 has been previously described to regulate splicing of the INS transcript, indicating that this regulatory mechanism also affects splicing of INS-IGF2. The identification of the INS-IGF2 read-through transcript specifically in tumor tissue but not in normal pancreatic tissue suggests that high expression of INS-IGF2 could be neoplasia­specific. These results may have potential clinical applications given that the read-through transcript could be used as a biomarker in insulinoma patients.

Transcriptomic Profiling of Tumor Aggressiveness in Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms.

OBJECTIVES: The aim of the study was to compare RNA sequencing data of sporadic nonfunctioning pancreatic neuroendocrine neoplasms (PNENs) to identify gene expression patterns that may be important for molecular differentiation of tumor aggressiveness. METHODS: RNA sequencing was performed on samples of sporadic nonfunctioning PNENs, grouped as tumors with mild behavior (nonmetastatic and Ki67 < 5%) or aggressive behavior (metastatic and Ki67 ≥ 5%), on an Illumina Genome Analyzer II platform. Bioinformatic analyses were performed on the resulting data. RESULTS: Of 22,810 identified transcripts from protein-coding genes, a set of 309 genes were significantly differentially expressed between the 2 groups, of which 166 were upregulated and 143 downregulated in the aggressive disease group. Among the top protein-coding upregulated genes, we found genes encoding proteins involved in DNA packaging, ability to taste, chromosome structuring, cytoskeleton structuring, and cell-cell signaling. Among the top protein-coding downregulated genes, we found genes encoding proteins involved in neuronal differentiation, cytoskeleton structuring, cell-cell signaling, and immunological processes. CONCLUSIONS: A higher degree of tumor aggressiveness in sporadic nonfunctioning PNENs seems to be associated with upregulation of genes involved in regulation of the cell cycle and cell division. Small sample size and lack of a replication set are limitations of this study.