Neuroendocrine tumors (NETs) are rare and heterogeneous neoplasms of epithelial origin arising from cells of the neuroendocrine system. A large population-based study estimated that the age-adjusted incidence of gastroenteropancreatic NETs (GEP-NETs) in 2012 was 3.56 per 100,000 persons in the United States while recent reports suggest that their overall incidence is progressively increasing over time [1], [2], [3]. In European countries the prevalence of GEP-NETs ranges from 2.1 to 6.6 cases per 100,000 population per recent reports [4]. NETs are mainly developed in the gastrointestinal or bronchopulmonary system or may rarely arise in other sites such as the ovaries and/or the urinary bladder. Although a number of NETs are capable of synthesizing and secreting biochemically active substances leading to distinct clinical syndromes (functioning tumors), the great majority are non-functioning [5]. Most of NETs are well differentiated and may display prolonged survival besides the presence of metastatic disease; however, a subset may exhibit an aggressive behaviour being associated with poor prognosis [5].

Biomarkers are alterations in the clinical, biochemical, histopathological and molecular components of the tumors that can be used for the diagnosis, prognosis and prediction of tumor behaviour and/or outcome of treatment [6]. Over the years, several circulating biomarkers have been developed for the early diagnosis and follow-up of patients with NETs [7]. In the beginning, the specific secretory products of functioning tumors were considered as the most relevant biomarkers to be included in the diagnostic process and to be utilized for prognostic and predictive purposes, as markers of treatment failure, cancer progression, or recurrence [7], [8]. However, as the majority of NETs are non-functioning and even functioning tumors could remain unrecognised for many years, it was necessary to develop general tumor markers that are produced by virtually all NETs. Chromogranin A (CgA) and neuron-specific enolase (NSE) have been the most important and most commonly used ones in the clinical practice so far but limitations in terms of assay reproducibility, sensitivity and specificity have been extensively documented [7], [9].

A United States National Cancer Institute summit, held in 2007 on NETs, reported biomarker limitations to be a crucial unmet need in the management of these tumors [10]. Indeed, current NET biomarkers represent a monoanalyte assessment of protein or amines that cannot reflect accurately the behaviour of these extremely heterogeneous neoplasms. Over the last years, novel techniques of multianalyte analysis of regulators of tumor biology detectable in blood have been developed and have been successfully employed in multiple malignancies such as breast and lung cancer. Multianalyte biomarkers including, circulating tumor cells (CTCs), circulating DNA (ctDNA), mRNA and micro-RNA (mi-RNA) have been recently investigated in NETs but mutations are not a prominent feature of these tumors and the results that support the clinical use of these biomarkers are relatively limited [6], [7]. Amongst these, the NETest, a multianalyte that analyses multiple gene transcripts in circulating blood, has been more extensively studied and proved to display significant sensitivity and specificity as a diagnostic and follow-up marker of treatment efficacy in both GEP-NETs and bronchopulmonary NETs that seems to integrate the optimal characteristics of the optimal biomarker [11⁎], [12⁎].

The purpose of this review is to provide information on the circulating biomarkers that have been used in daily clinical practice so far, as well as to discuss the findings regarding the novel promising diagnostic, prognostic and predictive biomarkers for NETs.