NET cancer, short for neuroendocrine tumor, is a type of cancer that grows from neuroendocrine cells, specialized cells found throughout the body that receive signals from the nervous system and respond by releasing hormones. These tumors can form in many organs but appear most often in the digestive tract, lungs, and pancreas. Once considered rare, NETs have been diagnosed at increasing rates over the past two decades, with the annual incidence roughly doubling from about 5 per 100,000 people in 2000 to over 8 per 100,000 in 2018.
Where NETs Develop
In adults, the most common location is the gastrointestinal tract, including the small intestine, rectum, and stomach. Pancreatic NETs are another well-known subtype. The lungs are a frequent site as well. In children and young adults, NETs tend to appear in the appendix or the lungs. Because neuroendocrine cells exist in nearly every organ, these tumors can technically arise almost anywhere, but the GI tract and lungs account for the large majority of cases.
Why NETs Are Often Found Late
Many NETs grow slowly and produce vague symptoms, or no symptoms at all, for years. A tumor in the small intestine might cause intermittent abdominal discomfort that gets attributed to other conditions. Non-functioning NETs (those that don’t release excess hormones) are especially easy to miss because there’s no obvious hormonal signal pointing to a problem. The biggest increases in diagnosis over the past two decades have been in early-stage, low-grade tumors, largely because imaging technology has improved and doctors are more aware of the disease.
Functioning Tumors and Carcinoid Syndrome
Some NETs actively secrete hormones, and these are called functioning tumors. The most recognized hormonal complication is carcinoid syndrome, which happens when a tumor (usually one that has spread to the liver) releases large amounts of serotonin and other substances into the bloodstream.
The hallmark symptoms of carcinoid syndrome are skin flushing and diarrhea. Flushing occurs in roughly 85% of patients with the syndrome, and diarrhea affects about 80%. Less commonly, 10% to 20% of patients experience wheezing or difficulty breathing, often during flushing episodes. Over time, the hormonal excess can damage heart valves, particularly on the right side of the heart. Cardiac involvement occurs in 60% to 70% of patients with carcinoid syndrome, caused by fibrous deposits building up on the heart valves.
How NETs Are Graded
Not all NETs behave the same way. Doctors grade them based on how quickly the tumor cells are dividing, measured by a marker called Ki-67 that reflects the percentage of cells actively reproducing. Grade 1 tumors have fewer than 3% of cells dividing, meaning they grow slowly. Grade 2 tumors fall between 3% and 20%. Grade 3 tumors exceed 20% and tend to be aggressive. This grading system is one of the most important factors in determining prognosis and choosing treatment.
A separate but related distinction exists between well-differentiated NETs (which still resemble normal neuroendocrine cells under a microscope) and poorly differentiated neuroendocrine carcinomas (which look highly abnormal and behave more like aggressive cancers). Grade 1 and 2 tumors are almost always well-differentiated, while Grade 3 tumors can be either.
Diagnosis and Imaging
The primary blood marker used to detect and monitor NETs is chromogranin A, a protein released by neuroendocrine cells. It’s elevated in the vast majority of certain NET subtypes: 100% of gastrinomas, 89% of pheochromocytomas, and 80% of small intestine NETs in one large analysis. Higher chromogranin A levels generally correlate with more advanced disease, with patients who have extensive liver metastases showing significantly higher concentrations. One important caveat: common acid-reducing medications (proton pump inhibitors) can raise chromogranin A levels 5 to 10 times above normal, potentially mimicking the levels seen in early-stage NETs.
For patients with suspected carcinoid syndrome, a 24-hour urine collection measuring a serotonin breakdown product called 5-HIAA is also used, though the blood test for chromogranin A is simpler to collect and often more informative.
The most powerful imaging tool for NETs is a specialized PET scan that targets somatostatin receptors on the surface of tumor cells. This scan detects NET lesions with a sensitivity of 80% to 100%, significantly outperforming conventional CT and MRI. In one study comparing bone metastasis detection, the specialized PET scan found 225 lesions where CT identified only 84. This imaging also helps determine whether a patient is a candidate for certain targeted therapies.
Treatment Options
Treatment depends heavily on the tumor’s grade, location, and whether it has spread.
- Surgery is the primary treatment for localized NETs and offers the best chance of cure. Even in cases with limited spread, removing the primary tumor and accessible metastases can significantly extend survival.
- Somatostatin analogs are the cornerstone of medical therapy for many NETs. These drugs mimic a natural hormone that slows hormone release and cell growth. Pooled data from over a dozen trials show that about 71% of patients experience improvement in diarrhea and flushing. Beyond symptom control, 55% of patients achieve stable disease, meaning the tumor stops growing. In a landmark clinical trial, patients treated with a long-acting somatostatin analog had a median time to tumor progression of 14.3 months compared to 6 months with placebo.
- Peptide receptor radionuclide therapy (PRRT) delivers targeted radiation directly to tumor cells by attaching a radioactive molecule to a compound that binds to somatostatin receptors on the tumor surface. The phase 3 NETTER-1 trial, published in the New England Journal of Medicine, showed a median progression-free survival of 33 months for patients with midgut NETs treated with PRRT, roughly doubling what the control group achieved.
- Other approaches include targeted drugs that block tumor blood vessel growth or cell signaling pathways, chemotherapy (mainly for high-grade tumors), and liver-directed therapies for patients with metastases confined to the liver.
Survival Rates
Survival varies enormously depending on the tumor type, grade, and stage. Data from the American Cancer Society on pancreatic NETs illustrates this range: the 5-year survival rate is 91% for localized disease, 64% for regional spread, and 19% for distant metastases. Across all stages combined, the 5-year survival is 48%. These numbers are specific to pancreatic NETs. GI NETs found in the small intestine or appendix, particularly low-grade ones, often have better outcomes. Grade 1 tumors that are caught early can behave almost like chronic conditions, with patients living for decades.
Genetic Risk Factors
About 10% of pancreatic NETs are linked to inherited genetic syndromes rather than arising spontaneously. The most common is MEN1 syndrome, caused by mutations in a tumor suppressor gene on chromosome 11. People with MEN1 develop tumors in multiple endocrine glands, often including the pancreas, parathyroid, and pituitary. Von Hippel-Lindau disease, caused by mutations in the VHL gene on chromosome 3, also raises NET risk alongside tumors in the kidneys, adrenal glands, and central nervous system. Rarer syndromes include neurofibromatosis type 1 and tuberous sclerosis complex. If multiple family members have been diagnosed with endocrine tumors, genetic testing can identify whether an inherited mutation is involved and guide screening for at-risk relatives.