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Neuroendocrine tumors (NETs) are infrequent neoplasms that originate from endocrine glands (parathyroid, pituitary, adrenal glands), from endocrine islets inside other glands (pancreas, thyroid), or from the endocrine cells dispersed throughout the digestive system and the respiratory tract.
They can be categorized depending on their origin into foregut (bronchial, gastric, duodenal, and pancreas), midgut (jejunal, ileal, appendiceal, and ascending/transverse colon), and hindgut (distal colon and rectum).
A characteristic feature of neuroendocrine cells, and subsequently of tumors derived from them, is the production of a wide range of biogenic amines, peptides, tachykinins, and prostaglandins. These neoplasms that generate an active product are often known by the specific term for each substance, such as for instance, insulinoma, somatostatinoma, glucagonoma, etc.
The excessive production of bioactive substances may determine the clinical presentation of the tumor, with carcinoid syndrome being the most typical and well-known. Carcinoid syndrome consists of a constellation of symptoms, such as episodic flushing, bronchospastic symptoms, secretory diarrhea and associated abdominal pain, due to an increased secretion of serotonin and other agents. This syndrome occurs in the presence of liver metastases as portal circulation enables the liver to clear the hormones before they can enter the systemic circulation.
Nevertheless, carcinoid syndrome is relatively uncommon and occurs in only 10 to 20% of patients. The most usual presentations of gastrointestinal NETs are recurrent abdominal pain and cramping, intermittent small bowel obstruction, and gastrointestinal bleeding. However, up to one-third of cases are asymptomatic and are diagnosed by accident.
The diagnosis of these tumors includes common forms of anatomic imaging such as computer tomography (CT) and magnetic resonance imaging (MRI) scans, to characterize the extent of the disease and assist with staging and planning therapy, as well as specific functional imaging techniques. These include indium-octreotide scintigraphy (OctreoScan) and PET-CT with 68Ga-DOTATATE. They provide evidence of the biological behavior of the tumor, and are specially recommended for the detection of regional and distant metastases.
Other diagnostic methods that must be considered are upper and lower endoscopy, both with standard techniques and with endoscopic ultrasound.
Since they were first labeled as carcinoid tumors by the German pathologist Siegfried Oberndorfer in 1907, there has been significant progress in NET-related biological and clinical research, and consequently, in the treatment options available for these tumors. Nevertheless, surgery remains the only curative method and should be considered for all patients if technically feasible.
Gastric neuroendocrine tumors:
Gastric NETs are divided into three categories with different biological behavior and prognoses. Management and treatment depend on the type of gastric NET:
The treatment of these tumors is controversial. Generally, for tumors smaller than 1-2 cm, endoscopic resection may be adequate, with endoscopic surveillance every 6-12 months. More aggressive techniques are rarely needed, but they must be considered for tumors larger than 2cm, which increases the risk for metastasis, extensive tumor infiltration of the gastric wall, poorly differentiated histology, and emergent bleeding.
Small intestinal neuroendocrine tumors:
Small intestinal NETs can occur anywhere from the duodenum to the terminal ileum, but they are most frequently found in the ileum within 60 cm from the ileocecal valve. They can be solitary tumors or multifocal (in 25% of affected patients). These tumors tend to produce both regional and distant metastases (37% and 27% respectively, on presentation), irrespective of size, even if they measure less than 1 cm.
The treatment for patients with nonmetastatic tumors consists in resecting the involved segment and its mesentery. The remainder of the small intestine should always be examined properly at the time of surgery, because of the high probability of multifocal tumors.
In patients with known metastatic tumors, resection of the primary tumor may be advised in order to reduce the potential of intestinal obstruction or bleeding, and abdominal pain. Nevertheless, this remains a controversial area.
Colorrectal neuroendocrine tumors (nonappendiceal):
Colonic and rectal NETs are slightly different. Colonic tumors are larger and more aggressive, with at least 40% metastatic tumors on diagnosis. They are most frequently right sided and are usually asymptomatic until they are locally advanced. By contrast, rectal NETs tend to be smaller and are usually localized on presentation.
The treatment for colonic NETs is similar to that for colonic adenocarcinomas. A formal partial colectomy and regional lymphadenectomy is recommended, except for small incidentally detected tumors completely removed with an endoscopic polypectomy. In this case, endoscopic surveillance alone can be considered.
In the case of rectal tumors, the treatment is similar. If the tumor is smaller than 1 cm and confined to the mucosa or submucosa (and most of them are), an endoscopic resection with negative margins is usually enough. However, tumors larger than 2 cm and those that invade the muscularis propria should be treated with radical surgical resection (low anterior resection or abdominoperineal resection). The treatment for intermediate-sized tumors is controversial. It is generally accepted that tumors without risk factors (elevated mitotic rate, lymphovascular invasion, etc.) can be treated with endoscopic resection, and tumors that show any risk factor should be treated with radical surgery.
Appendiceal neuroendocrine tumors:
Appendiceal NETs are usually asymptomatic and often detected during an appendicectomy. Their prognosis is best estimated by tumor size. Almost 95% of them are smaller than 2 cm and they have a low probability of having metastases on diagnosis.
Appendiceal NETs can be considered cured with only an appendicectomy if they:
By contrast, a formal right hemicolectomy is advised if the tumor:
The treatment for tumors between 1 and 2 cm in size is also controversial, and there is no clear evidence about whether or not a right hemicolectomy should be performed.