Bronchial NETs are essentially divided into typical, atypical, large-cell and small-cell lung NETs. This paragraph will concentrate on typical and atypical lung NETs. These tumours can produce almost any of the described hormones or amines in the body. The carcinoid syndrome including flushing, diarrhoea, cardiac fibrosis, wheezing and dyspnoea occurs in lung NETs but is usually a atypical variant and not quite similar to the syndrome in the small intestine. The syndrome is rarely related to production of serotonin and tachykinins but because of the lack of enzymes converting hydroxytryptophan (5-HTP) to serotonin patients show a prolonged flushing, headache, palpitation and lacrimation as well as broncho-constriction [4, 7]. Lung NETs may also produce Cushing syndrome due to ectopic adrenocorticotrophic hormone (ACTH) production or acromegaly due to ectopic growth hormone-releasing hormone (GHRH) secretion [4, 7, 14]. Besides these specific biomarkers, these tumours also produce CgA as well as prepro-gastrin and NSE. Thymic carcinoids are usually of the non-functioning type, but about 30 % of the patients can present the Cushing syndrome with increased secretion of ACTH or corticotrophin-releasing factor (CRF) [54–56].

Duodenal NETs (carcinoids) may secret gastrin and cause the typical Zollinger-Ellison syndrome with recurrent ulcers, diarrhoea and abdominal pain [20, 21]. The duodenal gastrinoma may be part of MEN-1 syndrome. Somatostatin-producing NETs are also found in the duodenum. These are usually not presenting any hormone-related symptoms, but histologically they present with psammoma bodies rather than the presence of somatostatinoma syndrome. Some of these tumours are part of the von Hippel-Lindau disease (VHL) [1–3]. Gastric NETs are divided into ECLoma type 1, 2 and 3 and are derived from ECL cells in the corpus fundus region of the stomach. Another type of gastric NETs is G-cell tumours of the antrum. Most antral carcinoids are producing not only gastrin but also ghrelin and sometimes serotonin [57, 58]. The type 1 ECL tumours are associated with chronic atrophic gastritis and present high levels of CgA and sometimes also histamine production and the atypical carcinoid syndrome. Type 2 tumours are associated with MEN-1, Zollinger-Ellison syndrome and hypertrophic gastropathy. Type 3 tumours are sporadic and are not associated with any distinctive gastric pathology. Type 1 and 2 tumours are sharing common hypergastrinaemia, whereas type 3 tumours are independent of any overt hormonal imbalance. All three subtypes of ECL tumours present elevated plasma chromogranin A levels [59–61].

Carcinoid syndrome is a typical clinical presentation of metastatic ileal carcinoid occurring in about 18 % of patients and is characterised by flushing, diarrhoea and abdominal pain [3, 4]. Less frequent events are carcinoid heart disease as well as broncho-constriction and pellagra-like skin changes. The syndrome is related to massive release of serotonin which is no longer metabolised in the liver. Other substances involved in the carcinoid syndrome might be tachykinins (neuropeptide K, substance B, NKA), prostaglandins and bradykinins [6, 7, 14]. Patients with carcinoid syndrome present with increased levels in the urine of the breakdown product of serotonin 5-HIAA, with levels between 100 and 3,000 μmol/24 h (ref. <50 μmol/24 h). The overall sensitivity and specificity of u-5-HIAA in the presence of carcinoid syndrome is 70 and 90 %, respectively [4, 7, 14, 62]. Therefore, this marker is the most frequently performed assay in the clinical setting of the carcinoid syndrome. High-pressure liquid chromatography (HPLC) with electrochemical detection is currently recommended to measure urinary 5-HIAA. In some laboratories automated assays using mass spectrometry are available. It has been recently suggested that plasma 5-HIAA might be a valid alternative to the collection of u-5-HIAA [63]. Some studies have demonstrated higher sensitivity (100 %) for the measurement of platelet poor plasma serotonin compared with u-5-HIAA in patients with small intestinal NETs [14]. However, there are large fluctuations in the plasma levels of serotonin depending upon food ingestion, time of the day, stress and sampling procedures. In addition, certain malabsorptive conditions including Whipple’s disease and celiac sprue may be associated with elevated urine 5-HIAA levels. It is also important that the patient gets strict diet instructions, avoiding plums, pineapples, bananas, eggplants, tomatoes, avocados and walnuts during the collection of urine. Certain medications made also interfere with the assay: paracetamol, fluorouracil, methysergide and naproxen. On the contrary levodopa, aspirin, ACTH, methyldopa and phenothiazine may give false-negative results. Somatostatin analogues are known to decrease levels of 5-HIAA. Serotonin plays a key role in the development of peritoneal and cardiac fibrosis with activation of the 5-HT2B receptor and the cascade of connected tissue growth factors. Reduction in plasma serotonin levels correlated with decreased incidence of carcinoid heart disease. Moreover, u-5-HIAA excretion also correlates with the severity of carcinoid heart disease and prognosis in patients with carcinoid syndrome. In the clinical practice, it is useful to have two consecutive 24 h collection of urine for measurements of 5-HIAA and take the mean value, but there is a strong argument to change to measurements of plasma 5-HIAA.