Epigenetic Morphology and Classification of Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are rare tumors, most commonly encountered in the small intestine, pancreas and lung. The mechanisms of NET tumorigenesis are not completely understood. Furthermore, it is challenging to predict which NETs will metastasize and have poor prognosis. Especially for pancreatic NETs, for which surgery is associated with significant risks, predicting metastatic behavior is of great importance to select patients for surgery. Last, in patients presenting with NET metastases, it can be difficult to determine the origin of the metastases, as NETs can arise in any organ of the body. The research presented in this thesis works on solving these challenges. In the first place, it is found that Menin, an endocrine tumor-suppressor protein, is absent in most small pancreatic NETs. Therefore, Menin might have a role in initiating sporadic pancreatic endocrine tumorigenesis. Patients with hereditary mutations in Menin have an increased chance of developing NETs, including duodenal NETs. A novel hypothesis on duodenal tumorigenesis is proposed. To predict behavior of pancreatic NETs, an international collaboration resulted in the largest NET biomarker study to date. It was found that telomeric phenotypes are the best biomarker of metastatic behavior. Importantly, telomere phenotypes can be determined preoperatively by endoscopic ultrasound biopsies. Last, an epigenetic predictive model is presented, that can predict the origin of metastases with high (>90%) accuracy. In conclusion, telomeric phenotypes and epigenetic profiles might improve the care of NET patients in the future.