Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms (Review)

Abstract

Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in 'liquid' biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors. Contents1. Introduction 2. Aim and search strategy 3. Currently available biomarkers 4. Potential novel biomarkers 5. Conclusions

Four decades of experience with carcinoid heart disease: An analysis of 84 patients

“…Then, patients at risk of CHD could be monitored more closely, whereas patients that are classified as low risk for developing CHD would have to visit the hospital less frequently, hence reducing both patient and hospital burden. A recent review by Ciobanu et al has summarized available biomarkers for neuroendocrine neoplasms and possible future biomarkers 43 . Unfortunately, there are currently no candidate biomarkers that show promising perspectives for the screening for CHD.…”

An Overview of Circulating Biomarkers in Neuroendocrine Neoplasms: A Clinical Guide

“…Different biomarkers are used to more specifically diagnose subtypes of functioning pancreatic NENs in combination with other diagnostic (CgA) and imaging tools [69,80]. These markers include insulin, somatostatin, glucagon, gastrin, vasoactive intestinal peptide (VIP), serotonin, adrenocorticotropic hormone (ACTH), catecholamines, calcitonin, growth factor, insulin growth factor 1, and prolactin.…”

“…mRNA is isolated from EDTA-collected whole blood samples and real-time PCR is performed to interrogate 51 genes with the aid of four different prediction algorithms [113]. The choice of these 51 genes was developed on tissue-based, blood-based, and literaturecurated panels of genes in order to define the expression profile of NENs [80,113]. In addition, these genes have been confirmed as bona fide neuroendocrine markers in a large dataset (11,232 samples) from The Cancer Genome Atlas (TCGA) [114].…”

“…These aspects can be very advantageous in the diagnosis of NENs, both to distinguish poorly differentiated NETs from non-neuroendocrine tumors and to identify different molecular subgroups [132][133][134]. However, little is known about circulating miRNAs in NENs (Table 3), due to the lack of standardized analysis methods and inconsistency between tissue and circulating signatures [21,59,80,135,136]. Moreover, necrosis in G1 and G2 NET is uncommon; thus, these tumors do not represent an adapted source of miRNAs [134,137].…”

Metastatic Neuroendocrine Neoplasms of Unknown Primary: Clues from Pathology Workup

“…In modern medicine, auxiliary molecular testing is gaining ground as a complementary analysis to aid in therapeutic decision making, as mutational screening panels may identify actionable variants in NENs not responsive to conventional treatments [23,58]. However, there are also diagnostic benefits of utilizing next-generation sequencing (NGS) in clinical routine, as NENs developing in different tissues may have disparate genetic backgrounds and thereby be of help when assessing NEN-UPs [59].…”