Current Perspective on the Pathogenesis of Small Intestinal Neuroendocrine Tumors: Progress in Biomarkers and Molecular Events

Abstract

Background: Neuroendocrine tumors of the gastrointestinal tract differ in their histopathologic and clinical presentation. Small intestinal neuroendocrine tumors (SI-NETs), representing only a small portion within gastrointestinal malignancies, are often associated with a delayed diagnosis due to their non-specific symptoms. The increased incidence of SI-NETs during the last decades demands earlier diagnosis and more effective treatment, which both rely on a better understanding on the underlying molecular mechanisms. Summary: The purpose of this review is to discuss the biomolecular changes responsible for the pathogenesis of SI-NETs, and potential biomarkers in the diagnostic and prognostic evaluation. Key Message A greater understanding of the molecular mechanisms that underpin the pathogenesis of small intestinal neuroendocrine tumors (SI-NETs) facilitates the classification, diagnosis and treatment of these relatively rare gastrointestinal malignancies. Practical Implications Currently, SI-NETs are diagnosed using histological examination and staining for various neuroendocrine markers. Genetically, SI-NETs are characterized by an absence of alterations to K-ras, p53 and DNA mismatch repair genes. Loss of chromosome 18, deletion of Smad2 and Smad4, and amplification of SRC, EGFR and PDGFR have been reported. Abnormal DNA methylation status, reflected by overexpression of DNA methyltransferase, higher methylation of the RASSF1A promoter and overexpression of histone H1x are also associated with SI-NETs. These tumors are also associated with fibrosis, possibly due to the high levels of serotonin and other fibrotic factors produced. Genetic studies have pinpointed genes that can differentiate SI-NETs from other neuroendocrine tumors (oxytocin receptor, G protein-coupled receptor 113, VMAT-1, CDX-2), enabling more accurate diagnosis. Paraneoplastic antigen Ma2, neurokinin A and the CART peptide are under investigation as prognostic biomarkers. There is, however, still an unmet need for more sensitive biomarkers for earlier diagnosis and for a more specific classification system that encompasses tumor histology and reliable predictors of clinical response.

A Call to Action: Intensify the Investigation of Relatively Rare Tumors of the Gastrointestinal Tract

“…Gastrointestinal NETs have been termed ‘carcinoid tumors' for over a century. In comparison with colorectal cancer, relatively little is known about the molecular events underlying the evolution of the small intestine tumors [6,7]. …”