Carcinoid tumors secrete vasoactive peptides and amines (such as serotonin and tachykinins) into the systemic circulation resulting in carcinoid syndrome (CS). CS is usually present in patients with GEP-NETs arising in the midgut (i.e., small intestine, appendix, and proximal colon), and less commonly in the pancreas and lung [3, 4]. CS rarely occurs in the absence of hepatic metastases, except when the tumor products drain directly into the systemic circulation, as in the case of lung NETs or patent foramen ovale [5].

CS is classified as typical, characterized by diarrhea, abdominal pain and flushing (95% of cases) [6, 7], due to the release of serotonin, and atypical (5%), in which the clinical picture is variable depending on the bioactive substances secreted (serotonin, tachykinins, prostaglandins and kallikrein).

Diarrhea has a chronic course, is mainly secretory, does not improve with fasting and it is associated with electrolyte imbalances. The stools are usually watery, due to an increased peristalsis and hypersecretion [8, 9].

Abdominal pain occurs in about half of patients with CS, it may be intermittent, crampy or dull and it is not relieved by defecation. Flushing is the most frequent symptom, accentuated by food and alcohol intake, physical exercise and emotional states.

The characteristics of the flushing are particular: face, neck and upper chest take on a red color with typically dry skin [10]. The flushing may be associated with transient hypotension and bronchospasm. The overproduction of serotonin, a feature of CS, if not treated effectively, can lead to complications [11] such as muscle wasting and proximal myopathy [12, 13], niacin deficiency [14] and cognitive disorders [15–18].

Carcinoid heart disease (Hedinger’s syndrome) is one of the most common and critical aspects of CS, present in 10–20% of patients at diagnosis. Hedinger’s syndrome causes thickening of the heart valves, altering cardiac function, cardiac fibrosis and consequent right heart failure [19–21]. Up to 50% of deaths related to CS are due to heart failure.

Atypical CS is characterized by prolonged flushing, bronchospasm, headache, watery eyes, wheezing, and hypotension. Atypical CS is due to the production of 5-hydroxytryptophan and histamine instead of serotonin [22]. The carcinoid crisis is the extreme manifestation of CS, it is life-threatening and is in fact considered an oncological emergency [23]. It is caused by the massive release into the circulation of amine after anesthesia, interventional procedures or intake of drugs [24]. The main features are hypotension (rarely hypertension), tachycardia, dyspnea and dysfunction of the central nervous system [25].

Gastrinoma occurs as a result of hypersecretion of gastrin, generally by a GEP-NET of the duodenum or pancreas and rarely by other NETs (i.e., thymus) [26]. Gastrinoma is the most common functioning pancreatic NET (P-NET) [27–30]. This tumor is sporadic, with duodenal localization, in 50–88% of cases, or occurs in the context of multiple endocrine neoplasias type 1 (MEN1) in 25–30% of the cases, with duodenal localization in 70–100% [1, 31]. In rare cases gastrinoma occurs in other abdominal non-pancreatic, non-duodenal (stomach, liver, bile duct, ovary) (5–15%) and extra-abdominal (heart, small cell lung cancer) sites [28, 32–34]. The syndrome is suspected in patients with peptic ulcers refractory to proton pump inhibitors and who complain of diarrhea. In fact, stomach acid hypersecretion, due to the production of gastrin by the neoplasia, causes the Zollinger-Ellison syndrome [27, 35–37]. The main symptoms are due to peptic ulcer disease or severe gastroesophageal reflux disease with abdominal pain (75–98% of cases), nausea/vomiting (12–30% of cases), heartburn (44–56% of cases), diarrhea (30–73% of cases) and weight loss (7–53% of cases) [27, 28, 35–38]. Only 33% of patients present with bleeding, obstruction, penetration, perforation, all complications of peptic ulcer at diagnosis [35, 36, 39]. Only in the presence of advanced disease, found in a small percentage of patients, are the symptoms and signs due to the tumor burden itself (i.e., pain, jaundice, bleeding) [27, 35, 36, 39].

Insulinoma is the most common functioning NET of the pancreas. In less than 10% of cases it is malignant, in approximately 10% of cases it is multiple, and in about 5% of cases it is associated with the MEN1 syndrome [27, 30, 40–43]. Tumor-induced hyperinsulinemia causes hypoglycemia. This leads to neuroglycopenia of the central nervous system (90%) which results in confusion, forgetfulness, coma, visual changes, altered consciousness or coma. Most patients also have symptoms due to the adrenergic stimulation secondary to the hypoglycemia (60–70%), such as sweating, tremors, palpitations, weakness, hyperphagia [27, 44–46].

These symptoms usually occur during fasting, delay in meals or during exercise. The presence of one of the above symptoms, especially associated with fasting or exercise must arouse a suspicion of hypoglycemia. Insulinoma should be suspected if Whipple’s triad is present: symptoms of hypoglycemia, documented hypoglycemia (plasma glucose ≤40 mg/dL) and relief of symptoms with glucose administration [31, 47].

Other well-described and established functioning P-NETs are a group called rare functioning tumors (RFTs) [27, 30, 48, 49]. RFTs represent less than 10% of all P-NETs [27, 50]. They can occur in the pancreas or in other sites such as the small intestine, lung or paraganglia [27, 29, 48–51]. Each of the established RFTs is associated with a distinct clinical syndrome reflecting the actions of the ectopically secreted hormone. The majority of patients with RFTs of the pancreas presents with metastatic disease (40–90%) to the liver [32].

There are other RFTs that can cause a specific syndrome, but the series reported in the literature are small. In addition, there is disagreement as to whether the characteristics described actually correspond to a real syndrome. Five possible RFTs are reported in P-NETs: secreting calcitonin, renin, luteinizing hormone (LH), erythropoietin and insulin-like growth factor II (IGF2) [27, 30, 48–51].

Calcitonin-secreting pancreatic endocrine tumors have been described as extremely rare (66, 67). Most are asymptomatic. When symptomatic, the most frequent symptoms are watery diarrhea (51.4%) and abdominal pain (35.1%). Most patients (59.5%) present with metastatic spread at the time of diagnosis [68].

In the literature very rare cases of LH-secreting pancreatic neuroendocrine tumors are reported. These cause libido alterations, menstrual abnormalities, hirsutism and infertility [67, 69]. Other cases of ectopic secretion of renin with hypertension [70], glucagon-like peptide 1 (GLP-1) [71] and IGF-2 [72] with hypoglycemia symptoms, and erythropoietin with polycythemia have also been reported [73]. Recently, a case of cholecystokinin-secreting P-NET with metastatic disease has been described, which presented with non-watery diarrhea, severe weight loss, gallbladder and peptic ulcer disease, but normal gastrin level [74].

Non-functioning NETs are not associated with the presence of circulating specific hormonal substances and, for this reason, do not manifest with characteristic symptoms. Non-functioning NETs give clinical signs when they are large enough to cause compression or invasion of adjacent organs or when they metastasize [75]. These tumors may still cause non-specific symptoms attributable to the tumor burden, such as abdominal pain (35–78%), anorexia and nausea (45%), weight loss (20–35%).

Less frequent signs are intra-abdominal hemorrhage (4–20%), jaundice (17–50%) or palpable mass (7–40%). Non-functioning NETs may secrete bioactive hormones or amines at subclinical levels [76–78] such as pancreatic polypeptide, chromogranin A, neuron-specific enolase, human chorionic gonadotrophin subunits, calcitonin, neurotensin or other peptides, but their serum concentrations are insufficient to induce specific symptoms [25, 27, 48, 50, 51, 79]. For these reasons, they are often diagnosed late or incidentally in the context of routine imaging studies performed for other conditions. In these cases the neuroendocrine origin of the tumor can be confirmed only at immunohistochemistry.