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Before the year 2000, gastroenteropancreatic neuroendocrine tumors (GEP NETs) were not well characterized [3]. The GEP NET incidence has increased worldwide over the last decades [2, 4]. Considering the constantly evolving imaging technology, small asymptomatic lesions in the gut can be identified [5]. NETs are a heterogeneous group found in different locations of the body, e.g., pancreas, foregut, midgut, hindgut, and lung [5, 6]. The regional distribution of NETs over the entire body is schematically displayed in Fig. 7.1. Gastroenteropancreatic (GEP) NETs are with two thirds the most common primary NETs [4, 7]. With one quarter of NETs, they occur in the lung as the second most location [2].

Fig. 7.1
figure 1

Overview of NET occurrence in the human body (Adapted of Yao) [4]. NETs are found all over the body; the gastropancreatic system is with 58% the most frequent region, followed by 27% NETs in the lung

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NETs arise from neuroendocrine-programmed cells, which are found throughout the body and are known to excessively produce and secrete molecules like neuropeptides and biologically active neuramines, such as insulin, serotonin, and somatostatin [7,8,9]. An overview of neuroendocrine-programmed cells is displayed in Fig. 7.2.

Fig. 7.2
figure 2

Schematic overview of neuroendocrine-programmed cells (Adapted from Tischler and DeLellis) [10]

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The classification of neuroendocrine tumors is based on size, tissue invasion, Ki67 index, and mitotic activity, according to the current WHO classification [5]. KI-67 is a proliferation marker and helps to determine tumor grade and prognosis [11].

There is still no balanced therapy for NETs [5]. Total resection in early stages is unchallenged in curative treatment compared to therapies, such as those with somatostatin analogues, radiotherapy, and chemotherapy, because they are still insufficient [4, 7, 12]. Knowledge on how to suppress hypersecretion or neoplastic growth could lead to a new therapeutic and palliative approach [13]. Due to the lack of mechanistic insights regarding this disease, many whole-genome sequencing approaches on NET patient tissues were initiated in order to identify mutations, which correlate with the development, prediction, or diagnosis of NETs [14]. The most frequent gene alterations in NET patients were found in the following genes: MEN-1 (encodes menin), DAXX (death domain-associated protein), ATRX (alpha thalassemia/mental retardation syndrome X linked), and mTOR (mammalian target of rapamycin) with the related pathway members [14,15,16,17].

7.1 MEN-1

NETs occur either sporadically or as manifestation of a syndrome, like the multiple endocrine neoplasia type 1 (MEN-1) syndrome [16]. A germline mutation in the MEN-1 tumor suppressor gene, located on the chromosome 11q13, causes this autosomal dominantly inherited condition [15, 16]. This gene encodes the 610 amino acid nuclear protein menin, which is associated with regulation of transcription, genomic stability, cell division, and cell cycle control [10, 18,19,20]. Over 450 different germline mutations have been identified to date. About two thirds of these mutations are predicted to lead to truncations on the protein [18]. Either truncations or missense in Men-1 leads to lower protein levels because of proteolytic degradation via the ubiquitin pathway [16, 21]. Mutations in MEN-1 are associated with a prolonged survival compared to patients without MEN-1 mutation [14].

7.2 DAXX/ATRX

Likewise, NET patients with mutations in DAXX/ATRX have a better survival rate [17, 22]. These mutations affect incorporation of the histone H3.3 complex into telomeres by inducing alternative lengthening of telomeres and chromosomal instability [17, 22].

7.3 mTOR Signaling

Some NET patients were reported to have mutations in the PTEN, PI3K, and TSC2, genes of the mTOR pathway [14]. It seems that these mutations are relevant only for few NET patients because alterations in expression of mTOR pathway members are found in most patients [14, 23, 24]. Therefore, whole-genome sequencing of NETs can help to identify patients which would benefit from therapy with mTOR inhibitors [14].

Chromosomal instability in NET patients is associated with tumor progression. As the extent of genomic changes seems to correlate with disease stage, indicating alterations accumulate during tumor progression [10, 19].

7.4 Biomarkers of Neuroendocrine Neoplasms

At the beginning of their formation, NETs usually do not show specific symptoms over a long time period. The low proliferation rate of most NETs might be an explanation for this phenomenon [25]. Due to their origin, NETs secrete different molecules. This might be a way to look for a tumor marker. Four biomarkers for NETs have been established: chromogranin A (CgA), synaptophysin (SYP), neuron-specific enolase (NSE), and urinary 5-hydroxyindole-3-acetic acid (5-HIAA) [26].

Neuroendocrine cells secrete their products via large dense-core or small synaptic-like vesicles. Those vesicles store proteins like CgA and synaptophysin and therefore serve as markers for neuroendocrine cells [11]. CgA is a member of the chromogranin family and is often observed to be elevated in serum of patients [27]. Immunohistochemistry for CgA can confirm the origin in the tissue [11]. It also seems that CgA is a prognostic marker because it positively correlates with disease progression, liver metastases, and treatment efficiency [8, 11].

For the histopathological diagnosis of NETs, CgA and synaptophysin have to be present [28]. SYP is a calcium-binding integral membrane glycoprotein [11]. It is present in epithelial and neuronal types [10]. SYP is expressed independently from other NET biomarkers [28].

Neuron-specific enolase (NSE) plays a role in glucose metabolism. This enzyme was shown to be present in thyroid and prostatic carcinoma, neuroblastoma, small cell lung carcinoma, carcinoid, gastropancreatic tumor, and neoplasms with a neuroendocrine differentiation [26, 29]. Based on its lacking sensitivity and specificity as biomarker, it is mostly used to confirm the diagnosis or to control the treatment efficacy during follow-up [29].

Serotonin is one of the most hypersecreted hormones in NETs. 5-Hydroxyindoleacetic acid (5-HIAA) has serotonin as substrate and is excreted via the urine, where high levels of 5-HIAA are detected in patients with NETs [30, 31]. Although tryptophan- or serotonin-rich food can elevate 5-HIAA levels, the specificity of this marker is about 88% in NETs [31].