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

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

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. 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. 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. 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.Peer reviewe

Modern Surgical Treatment and Genomic Profiling of Pancreatic Neuroendocrine Neoplasms - from the Operating Theater to the Gene Lab

Pancreatic neuroendocrine neoplasms (PNENs) comprise approximately five percent of neoplasms originating from the pancreas. Surgical resection is an important treatment option for PNENs because it alone offers the possibility of cure. To date, little academic study has been undertaken with regard to surgery for PNENs and therefore the scientific evidence underpinning operative decision-making in this area is limited. One major aim of this thesis was to investigate clinical outcomes of modern surgical treatment for PNENs, including laparoscopic surgery, vascular reconstruction, and resection for high-grade neuroendocrine carcinoma. This was undertaken by a retrospective review of medical records at the largest tertiary care hospital in Norway which provides surgical treatment of PNENs and analysis of data from the Nordic neuroendocrine carcinoma registry. Laparoscopic surgery for PNEN cases was technically feasible in the majority of cases and with acceptable operative morbidity and good long-term prognosis. For patients with locally advanced PNENs, open pancreatic surgery with vascular reconstruction was feasible with acceptable surgical morbidity and short-term prognosis. In patients with high-grade pancreatic neuroendocrine carcinoma, combined surgical treatment and chemotherapy improved survival compared with chemotherapy alone. At present, the clinical management of patients with PNEN is largely based on radiological staging and histopathological characteristics. However, the malignant potential of the individual tumor varies greatly and may not necessarily be predicted by histopathology. Thus, there is a need for better understanding of the geno-phenotypical relationship of these neoplasms. A second major aim of this thesis was to identify genomic imbalance and genomic expression patterns that may be important for molecular differentiation of tumor aggressiveness in sporadic nonfunctioning PNENs. This was investigated by G-band karyotyping, high-resolution comparative genomic hybridization and RNA sequencing. In sporadic nonfunctioning PNENs, the number of genomic imbalances correlated with cell proliferation, tumor size and metastatic status. Loss of genomic material from chromosomal band 11p11 appeared to represent a primary pathogenetic event due to its high prevalence in small tumors with low cell proliferation activity. In sporadic nonfunctioning PNENs, higher cell proliferation activity and metastatic disease were associated with upregulation of genes involved in regulation of the cell cycle and cell division, such as those encoding Wnt signaling pathway proteins. Overall, this thesis shows that selected cases of PNENs can be safely removed using modern surgical procedures. For the first time, and against prior assumptions, the data presented in this thesis supports the use of combined surgery and chemotherapy, as compared to chemotherapy alone, to improve overall survival of patients with high-grade pancreatic neuroendocrine carcinoma. Additionally, the thesis describes genomic imbalance and genomic expression patterns in sporadic nonfunctioning PNENs that could potentially contribute in prediction of the individual patient’s prognosis

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

Loss of 11p11 is a frequent and early event in sporadic nonfunctioning pancreatic neuroendocrine neoplasms

The pathogenesis of sporadic pancreatic neuroendocrine neoplasms (PNENs) is poorly understood. To gain insight into the genetic mechanisms underlying this tumor entity, we performed genome-wide screening of 16 surgical specimens from 15 patients with sporadic PNEN, combining G-band karyotyping and high resolution comparative genomic hybridization (HR-CGH). G-banding revealed abnormal karyotypes in 2 of 10 tumor samples analyzed. DNA copy number changes were detected in 13 samples, whereas three tumors showed a balanced genome. Gains were more frequent than losses in the nonfunctioning tumors (n=13). Common gains were scored at 5p12–13, 4q13–24, 5p15, 5q11–31, and 9q21–22. Common losses were scored at 11p11, 11p14–15, 11q23, 11p12–13, and 11q22. The average number of copy aberrations (ANCA index) was 12 for 13 nonfunctioning primary tumors, 4.8 for the nonfunctioning tumors with low Ki-67 (≥5%), 21.2 for the tumors with high Ki-67 (<5%), 2.5 for small tumors (<3.5 cm), and 17.8 for large tumors (≥3.5 cm). There was a statistically significant difference in the ANCA index between the groups defined by Ki-67 and tumor size. Nonfunctioning tumors with low Ki-67, no distant metastasis and small size had few aberrations detected by HR-CGH, but frequent loss of material from chromosomal band 11p11. The present study indicates the existence of distinct cytogenetic patterns in sporadic nonfunctioning PNEN. Loss of chromosomal band 11p11 might indicate a primary pathogenetic event in these tumors