Overview of Gastrointestinal and Pancreatic Neuroendocrine Tumors (NETs)

Neuroendocrine tumors (NETs) develop from neural crest cells in the

• Gastrointestinal (GI) tract

• Pancreas

• Pulmonary bronchi

• Genitourinary tract

More than 90% of NETs develop in the GI tract in 3 sites: the appendix, ileum, and rectum (1). About 7% of NETs originate in the pancreas. The remainder develop in the lungs and rarely in the genitourinary tract or elsewhere.

Although NETs are often benign or only locally invasive, those affecting the ileum or a bronchus are frequently malignant. Malignant tumors range between well differentiated and poorly differentiated, with corresponding variability in aggressiveness. They typically spread to the liver and/or regional lymph nodes, although other metastatic sites are possible.

NETs can be

• Endocrinologically inert

• Endocrinologically active (produce hormones)

The likelihood that a tumor will be endocrinologically active varies with its site of origin, being highest for tumors originating in the ileum and proximal colon (40 to 50%) (1). The likelihood is lower with bronchial tumors, lower still with appendiceal tumors, and essentially zero with NETs of the rectum.

Endocrinologically active gastrointestinal and pancreatic NETs secrete a variety of hormones and other proteins. Some of these tumors are named for the predominant hormones they secrete (see table Pancreatic Endocrine Tumors). These include

• Gastrinomas: Hypersecrete gastrin, stimulating gastric acid secretion and causing ulcers

• Vipomas: Hypersecrete vasoactive intestinal peptide, causing diarrhea

• Glucagonomas: Hypersecrete glucagon, leading to diabetes

• Insulinomas: Hypersecrete insulin, causing hypoglycemia

Other rare NETs may hypersecrete somatostatin, adrenocorticotropin hormone (ACTH), or growth hormone–releasing factor (GRF). When endocrinologically active, gastrointestinal NETs secrete serotonin, histamine, and other hormones. Hypersecretion of these substances can cause autonomic, neuromuscular, and mental status changes that together make up the carcinoid syndrome. Tumor seeding beyond the portal circulation, such as with liver metastases from a gastrointestinal (predominantly midgut) NET, is a prerequisite for the carcinoid syndrome since the liver inactivates the causative peptides secreted by primary NETs.

Some of these clinical syndromes can also occur in multiple endocrine neoplasia (MEN syndrome), in which tumors or hyperplasia affects ≥ 2 endocrine glands, usually the parathyroids, pituitary, thyroid, or adrenals.

Endocrinologically inert NETs are suspected because of their symptoms and signs (eg, pain, luminal bleeding, gastrointestinal obstruction). They can be detected by angiography, CT, or MRI. Small-bowel NETs may exhibit filling defects or other abnormalities on barium radiographs. Definitive diagnosis and grading are determined histologically after biopsy or resection.

Staging evaluation typically includes imaging with MRI (probably preferred over CT scan) and sometimes imaging with somatostatin receptor-based imaging techniques (eg, gallium Ga68 dotatate PET/CT), which can be useful in detecting endocrinologically inert tumors as well (2, 3).