Gastrointestinal neuroendocrine tumors (NETs), sometimes referred to as gastrointestinal carcinoid tumors, are rare cancers that can arise in the stomach, intestines, rectum, appendix, or other portions of the gastrointestinal (GI) system.

This type of cancer is most commonly diagnosed in people in their 60s and rates are similar between males and females. Though the incidence of GI NETs is low, it is rising, with about 8,000 people diagnosed with the condition every year. However, the prevalence of GI NETs, the number of people living with a NET, is quite high, due in part to the slow growing nature of most NETs. Survival rates vary significantly by stage and primary site.

Several treatments are available for gastrointestinal NETS including surgical removal of tumors, radiation therapy, chemotherapy, hormone therapy, and other therapies that target the cancer. Around 94% of people with gastrointestinal NETs survive five or more years after diagnosis.

Gastrointestinal NETs are cancers that develop in the digestive tract. They arise most commonly in the small intestine and the rectum, but they may appear anywhere from the esophagus to the anus.

Gastrointestinal NETs specifically affect neuroendocrine cells. In healthy people, neuroendocrine cells respond to signals from the nervous system by producing and releasing hormones that aid digestion. When neuroendocrine cells within the GI system mutate, they may begin to multiply uncontrollably, leading to the formation of a gastrointestinal NET. The cells may also release more hormones than they normally should.

There are several important characteristics of GI NETs that determine the pace of growth and allow your medical team to select the best treatment approach. These features include the degree of differentiation, grade, stage, and functional status.

The degree of differentiation and grade are microscopic features of the cancer cells and can help predict how fast a cancer cell grows. Well-differentiated and low-grade (grade 1 or 2) tumors tend to grow more slowly, whereas poorly differentiated and high grade (grade 3) tumors tend to grow more quickly.

Stage refers to where the cancer has spread in the body and is based on features of the primary tumor (where the cancer started), whether the cancer has spread to lymph nodes, and whether the cancer has spread to other locations in the body.

Functional status refers to whether a GI NET secretes hormones (that can be measured in the blood or urine) associated with symptoms caused by those hormones—for instance, carcinoid syndrome is associated with serotonin secretion, flushing, and diarrhea.

Gastrointestinal NETs may develop when neuroendocrine cells within the GI tract experience mutations. There is no single known cause of GI NETs, and research about the biology of NETs is ongoing.

Rarely, patients with GI NETs inherit a genetic condition that predisposes them to having a GI NET. These include:

• Multiple endocrine neoplasia, type 1
• Neurofibromatosis type 1
• Tuberous sclerosis complex
• von Hippel Lindau disease
• Familial small intestinal neuroendocrine tumor

Because gastrointestinal NETs are often slower-growing than other types of cancer, sometimes forming over a period of months or years, many people don’t experience any symptoms. Doctors may discover the condition when treating another health problem.

If people do experience symptoms, however, they may be vague and could be associated with any number of other medical conditions. Those symptoms include:

• Fever
• Nausea
• Vomiting
• Diarrhea
• Constipation
• Blood in the stool (red or black)
• A flushed face
• Abdominal cramps
• Abdominal pain
• Bloating
• Unexplained weight loss
• Rectal bleeding
• Rectal pain
• Anemia
• Fatigue
• Shortness of breath
• Wheezing
• Jaundice (yellowing of the eyes and/or skin)
• Rapid heartbeat
• Rashes
• Confusion
  

Doctors can diagnose the condition after obtaining a medical history, performing a physical examination, and ordering diagnostic tests.

When doctors obtain a medical history, they will ask about any inherited disorders, if there is a history of gastrointestinal problems or changes in bowel habits, or if there is a family history of cancer.

During a physical exam, doctors may look for facial flushing, jaundice, or other skin abnormalities. They may also press on the abdomen to check for pain or tenderness.

The following diagnostic tests are useful in determining if an individual has a gastrointestinal NET:

• Blood tests. Tests that evaluate blood counts, kidney function, liver function and electrolytes are often evaluated. Hormones and tumor markers are also sometimes tested.
• Urine tests. Urine samples may be analyzed for hormones.
• Upper endoscopy. When a tumor is suspected in the upper GI tract, doctors may use a long, flexible tube with a camera on its end to locate and view the esophagus and stomach. If a tumor is discovered, they can perform a biopsy during the procedure.
• Colonoscopy. Similar to an upper endoscopy, a long flexible tube with a camera on its end is used to view a tumor in the rectum and colon. During colonoscopy, a suspicious area can be biopsied.
• Imaging studies. Doctors may order CT scans, MRIs, ultrasounds, or PET scans. A type of PET scan known as Somatostatin Receptor Imaging (SRI) may be used to diagnose gastrointestinal NETs. In SRI, a small amount of Gallium-68 (Ga-68) DOTATATE, a radioactive substance known as a radiotracer, is injected into a vein. The Ga-68 DOTATATE attaches to receptors found on the surface of NET cells, making them stand out on this type of PET scan.
• Biopsy. When blood tests, urine tests, or imaging study results point to a tumor, doctors will biopsy the tissue, then have the cells analyzed to check for the presence of gastrointestinal NETs. Biopsies can be performed via endoscopy or by inserting a needle through the skin using CT or ultrasound as a guide.

There are a range of treatment options for individuals diagnosed with this type of cancer:

• Watchful waiting. Some gastrointestinal NETs are very slow-growing, and doctors may recommend a watch-and-wait approach, rather than more invasive treatments. The patient’s health will be monitored at regular intervals with blood tests and imaging studies. If/when the tumor grows, treatment will be recommended.
• Surgery. Doctors remove the tumor and a margin of healthy tissue to ensure that all of the cancer has been removed. For many people, this procedure is curative. If it isn’t possible to surgically remove the entire tumor—if it is too large or has spread to other body parts, for example—doctors may still recommend removing a portion of the mass, which may limit unwanted hormone production.
• Liver-directed therapy. These involve treatments directed at NET liver metastases and include microwave ablation and embolization (bland embolization, chemoembolization, and radioembolization), which are approaches to block the blood vessel supply to tumors.
• Radiation therapy. High-energy radiation beams or radioactive medication, including radioligand therapies like ¹⁷⁷Lu-Dotatate, may sometimes be used to treat gastrointestinal NETs. When surgery isn’t possible, this may be the primary treatment. Other times, it may be offered after surgery to ensure that any remaining cancer cells are destroyed.
• Chemotherapy. This treatment won’t eradicate gastrointestinal NETs, but if the cancer spreads to other body parts, chemotherapy drugs may help to manage the condition.
• Hormone therapy. The prescription drugs octreotide or lanreotide are somatostatin medications that may help to limit the production of hormones and can slow the growth of NETs.
• Targeted therapy. For people with advanced disease, a medication called everolimus may help to control the growth of gastrointestinal NETs. Other targeted therapies are being evaluated in clinical trials.

Most people—about 94%—who are treated for gastrointestinal NETs survive 5 years or longer after their diagnosis, but the differentiation, grade, and stage will affect the prognosis. If the cancer spreads to distant parts of the body, for example, only about 67% of people survive 5 years or longer after diagnosis.

“Yale is a high-volume referral center for NETs and has experts across multiple disciplines, including medical oncology, surgical oncology, nuclear medicine, pathology, radiology, endocrinology, and interventional radiology,” says Pamela Kunz, MD, a Yale Medicine medical oncologist and expert in NETs. “Our Yale NET team works collaboratively to tailor the treatment to the patient. We also have a unique NET Survivorship program that helps patients focus on quality of life, nutrition, physical activity, and mental health.”