Gastroenteropancreatic neuroendocrine tumors




Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare and complex neoplasms that present many clinical challenges. Most GEP-NETs are sporadic, but they can be multiple and a component of a familial syndrome. Assessment of the location and extent of GEP-NETs is crucial for management and a number of novel imaging modalities are under evaluation with the principal goal of increasing sensitivity for the detection of micro-metastases while retaining specificity. The appropriate diagnosis and treatment of neuroendocrine tumors often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Management strategies include surgery, radiological intervention, cytotoxic chemotherapies, somatostatin analogs and novel biological agents such as sunitinib and everolimus. Other biological agents, new chemoteraphy regimens and somatostatin-tagged radionuclide therapies are also under investigation. In spite of this, comparison between therapeutic modalities is currently difficult. Further studies are warranted to individualize and optimize the diagnosis and treatment of these tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), also known as carcinoids and islet cell tumors, are tumors derived from neuroendocrine cells that can occur anywhere along the gastrointestinal tract and comprise a heterogeneous family of neoplasms with a wide and complex spectrum of clinical behavior. These tumors have been considered rare diseases, although the most recent data from the US Surveillance Epidemiology and End Results show an impressive increase of more than 400% in the incidence of this disease over a period of 29 years, rising from 1.09 per 100,000 population in 1973 to 5.25 per 100,000 population in 2004. GEP-NETs are more prevalent than many other tumors of the gastrointestinal tract, including stomach and pancreatic carcinomas combined. Age at diagnosis is generally younger than for carcinomas (5th decade) and they may arise sporadically or as a result of hereditary predisposition syndromes such as multiple endocrine neoplasia type 1, Von Hippel-Lindau’s disease or neurofibromatosis type 1.

GEP-NETs have traditionally been divided into foregut (esophagus, stomach, proximal duodenum, liver and pancreas), midgut (distal duodenum ileum, jejunum, ascending colon and proximal two thirds of transverse colon) and hindgut tumors (distal third of transverse colon, descending colon, sigmoid colon and rectum).

Survival of patients with GEP-NETs depends on stage and histology. Patients with well- and moderately-differentiated distant metastases have a 5-year survival probability of 35%; conversely, in patients with poorly-differentiated distant metastases, the 5-year survival probability drops to only 4%.

Treatment has two objectives: 1) remove the tumor, or, alternatively, reduce or stop the growth and spread of it; and 2) relieve symptoms of excessive hormone production.


GEP-NETs are characterized by their ability to produce, store and secrete a large number of peptide hormones and biogenic amines which can lead to the development of distinct clinical syndromes. Based on this, GEP-NETs are broadly subdivided into “functional” or “non-functional” tumors (with or without a clinical syndrome attributable to hormonal hypersecretion, respectively). Most GEP-NETs do not secrete biologically active substances and present fairly late with symptoms of mass effects or distant metastases. Among the “functional” tumors, each of these secreted substances causes a specific clinical syndrome, including carcinoid, Zollinger-Ellison, insulinoma, Verner-Morrison, and glucagonoma syndromes. Specific markers for these syndromes are basal and/or stimulated levels of urinary 5-hydroxyindoleacetic acid, serum or plasma gastrin, insulin, vasoactive intestinal polypeptide and glucagon, respectively. General markers such as chromogranin A, pancreatic polypeptide, serum neuron-specific enolase and subunit of glycoprotein hormones have been used for screening purposes in patients without distinct clinical hormone-related syndromes. The most important general circulating tumor marker is chromogranin A, expressed in 80-90% of all patients with GEP-NETs. Chromogranin A determination is also useful for staging, prognosis and follow up, since the serum concentration correlates to the tumor mass.


Surgery is the only potentially curative therapeutic strategy in localized disease. Radical oncological surgery is indicated except for small carcinoids (<2 cm) of the stomach, appendix or rectum, in which more conservative surgical or endoscopic resections may be appropriate due to their low malignant potential. Small pancreatic insulinomas also have a very good prognosis (90% are benign tumors) and tumor enucleation is generally sufficient. No adjuvant therapy is recommended in completely resected, well-differentiated localized GEP-NETs. Adjuvant chemotherapy with platinum and etoposide may be considered in poorly-differentiated tumors.

Surgery also plays a major role in advance disease. Surgery of metastasic disease is recommended if complete resection is feasible. Major cytoreductive therapy with palliative purposes may be considered even if R0 is not achievable in patients with extensive liver metastasis and hormonal syndrome refractory to medical therapy. Prophylactic cholecystectomy to prevent cholelithiasis is recommended in patients undergoing surgery if treatment with somatostatin analogs is anticipated. Surgery of the primary tumor may be performed in selected patients to avoid obstruction due to the neoplasm or to the fibrotic reaction commonly associated with small-bowel carcinoids.

When a functioning tumor is diagnosed before surgery, there is a risk of carcinoid crisis when the tumor is operated. This should be prevented by the administration of continuous i.v. octreotide at a dose of 50 mg/h for 12 h prior to and at least 48 h after surgery. Boluses of 100-200 mg octreotide can be given as required. It is also important to avoid drugs that release histamine or activate the sympathetic nervous system. Similarly, prophylaxis with glucose infusion for insulinoma surgery, proton pump inhibitor and octreotide for gastrinomas may be required.