Somatostatin is a small regulatory peptide hormone, which is distributed in the central and peripheral nervous system, endocrine glands, immune system and gastrointestinal tract. Two active forms of somatostatin are known, one consisting of 14 amino acids and the other of 28 amino acids.

Generally somatostatin is an inhibitory hormone which inhibits the release of several secondary hormones. The actions of somatostatin are mainly located to the pituitary where the secretion of growth hormone and TSH is inhibited as well as in the gastrointestinal system, where the release of numerous of different gastrointestinal and pancreatic hormones is suppressed. Additionally somatostatin modulates the gastrointestinal motility, suppresses the exocrine action of pancreas as well as inducing apoptosis.

The classification of NENs has been confusing and to date no general consensus has been agreed upon. Several different approaches have been attempted in order to classify the heterogeneous NENs to ensure optimal prognostic stratification and treatment schemes. Yet no universal classification for all NET sites is available. Because NENs predominantly arise in the gastroenteropancreatic or bronchopulmonary system, the following segment will deal mainly with classification of NETs from these organ systems.

In general NENs get classified by histology, grading, proliferation, anatomic site of origin, hormone secretion and/or extent of disease. Because many of the characteristics of the NETs are organ/site specific, location of the primary site can be a relevant stone in the therapy scheme. Therefore a classification by site of origin can be helpful in the clinical handling. The NETs are commonly divided into foregut, midgut and hindgut tumours based upon their embryonic segments and similar biological behaviour. NETs located in the small intestine and proximal colon (midgut) are often associated with typical carcinoid symptoms caused by serotonin hypersecretion, whereas NETs in the distal colon and rectum (hindgut) are usually non-functional [2, 15, 16]. Pancreatic and bronchial NETs (foregut) can be associated with hormone hypersecretion, but can be non-functional as well [2, 15, 16].

NETs can be histologically distinguished in well-differentiated NETs, poorly differentiated NECs and mixed adeno-neuroendrocrine carcinomas [17, 18]. The well-differentiated NETs are divided into low-grade and intermediate NETs dependent on the cell morphology, mitotic rate and/or Ki67 index of “hot spots” (Table 5.3). The Ki-67 index plays an important role in the NET classification, due to the good correlation of Ki-67 index and survival [19–22]. Additionally the Ki-67 index has proven to be an independent prognostic factor for survival, regardless of disease extent [23–27]. However, no significant difference in outcome between G1 and G2 carcinoids has been noted. The more aggressive poorly differentiated NECs are distinguished from the NETs using Ki-67 index/mitotic rate as well as showing a different pathological appearance. Additionally the NECs show a more rapid course with shorter survival and are generally treated with a platin-based chemotherapy scheme (Table 5.4) [28].

The World Health Organisation guidelines provide a classification to the extent of the disease using the tumour-node-metastasis (TNM) staging. Due to the vast biological diversity of NETs, the extent of the disease alone does not provide an adequate risk stratification or survival data. Many NETs have already metastasised by the time of first diagnosis, making a stratification based solely on the TNM system inadequate. For example, NETs of unknown primary are by definition stage IV in the TNM system and the histological grade may prove the only prognostic parameter.

Functionality may have an impact on the prognosis, yet the biological behaviour of most functioning NETs get defined by grade and stage. The clinical symptoms caused by hypersecretion of hormones define the division in functioning or non-functioning NETs. The immunohistological staining is not a defining criterion, only the presence of typical symptoms. Yet a functional tumour may be treated differently than a non-functional; therefore the presence of hormonal production should be included in the tumour nomenclature.

ENETs have come up with a proposal for the stratification of GEP-NETs, which combines TNM stages, grade and growth features (Table 5.4), and suggest potential treatment for the respective groups [28–33].

Due to the short half-life of somatostatin in human serum of 2–3 min caused by rapid enzymatic degradation, new somatostatin analogues with longer half-lives were necessary. The development led to the cyclooctapeptide octreotide, which still is very much in clinical use today. The “cold” octreotide and lanreotide are used in the treatment of acromegaly as well as antiproliferative therapy and symptom control of NETs. There are short-acting as well as long-acting products available.

The cyclic peptide additionally served as lead structure for most of the later-developed somatostatin analogues such as tyrosine3-octretotide (TOC), tyrosine3-ocreotate (TATE) and naphthylalanine3-octreotide (NOC). Octreotide and octreotide derivatives show a general high affinity to sstr2 with varying affinity to the other somatostatin receptor subtypes [34].

The radiolabelled somatostatin analogues generally consist of a biological active part, usually octreotide, TOC or TATE coupled with a chelator complex (i.e. DTPA, DOTA, EDDA/HYNIC) and a gamma emitting radiometal. The internalisation of the radioactive ligand-receptor complex with intracellular entrapment of the radiometal is considered the mechanism enabling tumour imaging by good scintigraphic tumour-to-background ratio, especially in delayed images.

With the indium-111-labelled DTPA-octreotide (OctreoScan), the first commercially available tracer enabling visualisation of in vivo somatostatin receptor distribution came on the market and still is the gold standard within gamma scintigraphy. Later DOTA- and HYNIC/EDDA-conjugated analogues, new tracers, found their way into the clinical routine. ⁶⁸Ga-DOTA-labelled derivatives prove the best imaging modality available, because of the superior qualities of PET/CT imaging. However, this modality is still restricted to only a few specialised centres and at time being no PET tracers are registered for clinical use, whereas three different tracers are registered for use in the generally widespread gamma scintigraphy.