6.8 Somatostatinoma

Somatostatin was isolated in 1973 by Paul Brazeau in Roger Guillemin’s laboratory. It was found to have a widespread distribution, not only in the hypothalamus and brain but also in the gastrointestinal tract. Sixty-five per cent of the body’s somatostatin is in the gut, mostly in the D cells of the gastric and intestinal epithelium. It is also present in the myometric and submucosal plexuses. The highest concentration is in the antrum of the stomach and there is a gradual decrease of concentrations down the gastrointestinal tract. Five per cent of the body’s somatostatin is in the pancreas.

Infused somatostatin, which has a short half-life of 3 min, has a large number of actions on the pituitary gland, the endocrine and exocrine pancreas, gastrointestinal tract, other hormones, and on the nervous system (Box 6.8.1). Among its various actions of importance in the gastrointestinal tract is the inhibition of gastrin and cholecystokinin (CCK). In the pancreas, insulin and glucagon are inhibited. Nonendocrine actions include inhibition of gastric acid secretion, pancreatic exocrine function, gall bladder contraction, and intestinal motility. Intestinal absorption of nutrients, including glucose, triglycerides, and amino acids, is also inhibited (1).

Somatostatin exists in two main forms, as a 14-amino acid peptide (somatostatin 14) present mainly in the pancreas and the stomach, and as a 28-amino acid peptide present mainly in the intestine. Somatostatin 14 is the peptide present in enteric neurons.

Somatostatin receptors are present on many cell types, including the parietal cells of the stomach, G cells, D cells themselves, and cells of the exocrine and endocrine pancreas. A large number of tumours also have somatostatin receptors and these include pituitary adenomas, endocrine pancreatic tumours, carcinoid tumours, paragangliomas, phaeochromocytomas, small cell lung carcinomas, lymphomas, and meningiomas. Five different somatostatin receptors (SSTRs) have been cloned (SSTR1–SSTR5) and all are on different chromosomes. These have a varying affinity for somatostatin 14 and somatostatin 28 and a varying tissue distribution with SSTR2 and 5 being predominant in the pituitary (2).

Somatostatin can act either as an endocrine hormone or in a paracrine or autocrine way. It probably also has luminal effects in the gastrointestinal tract. Lastly, it can act as a neurotransmitter (3).

Somatostatinomas are rare tumours with an estimated incidence of about 1 in 40 million. In total, over 200 have been described. They may be sporadic (90%) or familial (10%). Two main types exist: pancreatic somatostatinomas (56%), which are large tumours often associated with features of somatostatin excess; and duodenal tumours (44%), which are usually small and more amenable to surgical resection (6). They have also been described in the jejunum and cystic duct. The two types are compared in Table 6.8.1. They are infrequently associated with multiple endocrine neoplasia type 1 syndrome (7%), neurofibromatosis type 1, or Von Hippel–Lindau syndrome.

Somatostatinoma syndrome was first described in 1977 (8). Over 100 such cases have now been reported with features as in Box 6.8.2. The syndrome consists of cholelithiasis, the cause of which is multifactorial, including suppression of CCK production which results in impaired gallbladder contractility. High levels of somatostatin also inhibit bowel transit, which alters bowel flora, thus increasing bile acid reabsorption and this is associated with super saturated bile (9). Mild diabetes occurs and has often been present for many years before diagnosis. It is probably due to suppression of insulin secretion. Diarrhoea and steatorrhoea also occur and relate to the inhibition of pancreatic exocrine function. Hypochlorhydria relates to the inhibition of gastric acid secretion and gastrin. Anaemia, abdominal pain, and weight loss are also present and are nonspecific. They are probably related to the size of the tumour, which is usually large, and also to the fact that it is malignant. Those tumours are often diagnosed late and distant metastases may be present in lymph nodes, liver, or bone (55% are in the head of the pancreas).

Plasma and tissue levels of somatostatin are elevated and levels are higher in pancreatic as opposed to duodenal somatostatinomas. These somatostatin-secreting cells often also secrete ACTH, calcitonin, insulin, or some other peptides. This means that Cushing’s syndrome, flushing, or hypoglycaemia (if there is cosecretion of insulin) may be present (10).

Duodenal somatostatinomas tend to be smaller and present earlier. The vast majority occur near the ampulla of Vater where they tend to cause obstructive biliary disease (NFI) (39%). Some are associated with neurofibromatosis type 1 and some are occasionally associated with phaeochromocytoma. Radiologically they can be difficult to diagnose. This may need endoscopic techniques. At presentation paraduodenal lymph nodes are involved because there is a high malignancy rate, although this is usually low grade. None of the duodenal somatostatinoma patients have developed the full-blown somatostatinoma syndrome but diabetes and gall stones have been noted in some cases.

Histologically these are psammomatous tumours. Treatment is with surgery if this is feasible, chemotherapy, and, if necessary, hepatic embolization. Somatostatin analogues may lower somatostatin levels and improve symptoms (such as diarrhoea) of both types of somatostatinoma if metastases are present.