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

Abstract

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.