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

The most common anatomic sites of NETs of the GI tract are the rectum, small intestine, and pancreas (1). In addition to the GI tract, NETs develop in the lungs and rarely in the genitourinary tract or elsewhere.

Neuroendocrine neoplasms (NENs) are classified as either well-differentiated neuroendocrine tumors (NETs), grades G1 to G3 based on mitotic rate and Ki-67 proliferation index (20 mitoses/2 mm² and Ki-67 > 20% for G3), or poorly differentiated neuroendocrine carcinomas (NECs), which include small-cell and large-cell subtypes with high proliferative rates (2). Metastases typically spread to the liver and/or regional lymph nodes, although other metastatic sites are possible.

NETs are further classified by whether they secrete hormones or are nonfunctioning, which significantly impacts clinical presentation and management. 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, adrenocorticotropic 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) type 1, 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 multiphase computed tomography (CT) of the abdomen and pelvis and/or a gadolinium-enhanced magnetic resonance imaging (MRI) of the abdomen 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 (3). Staging of NETs uses the American Joint Committee on Cancer (AJCC) tumor, nodes, metastases (TNM) system, which includes specific staging tables for well-differentiated NETs of the following anatomic sites: stomach; duodenum and ampulla or Vater; jejunum and ileum; pancreas; appendix; and colon and rectum (2). NECs, which are poorly differentiated, are staged according to organ-specific criteria for non-neuroendocrine carcinomas.