Neuroendocrine tumors (NET) arise from endocrine (hormone producing) cells in various organs in the body, including the gastrointestinal tract, lungs, adrenal glands, and thyroid. These endocrine cells bear microscopic similarities to neurons (nerve cells) and interact with the nervous system: hence the term ‘neuroendocrine’.
NETs range in behavior from very slow growing to highly aggressive. Microscopic features on a tumor specimen (biopsy or surgical tissue) can help to categorize these tumors. Well-differentiated tumors resemble normal endocrine tissues and are less aggressive than poorly differentiated tumors, in which the normal tissue architecture is lost. In fact, poorly differentiated tumors are called neuroendocrine carcinomas (NEC) rather than neuroendocrine tumors (NET). Tumor grade refers to the number of dividing cells in the tumor specimen and can be measured by counting the number of cells undergoing mitosis (mitotic rate) or the ki-67 proliferative index. For gastrointestinal NETs, low grade (G1) is defined as ki-67% of 0-2%, intermediate grade (G2) as 3-20%, and high grade (G3) as >20%. A small minority of well-differentiated NETs are high grade, but all poorly differentiated NECs are high grade.
NETs arising in the gastrointestinal tract and lungs used to be known as ‘carcinoid tumors’, and the term persists in the medical literature.
A common question is whether low-grade NETs can be benign. All tumors that have spread to lymph nodes or other organs are, by definition, malignant. However, some low-grade tumors are small and non-invasive. Depending on where they originate, these tumors can have an extremely low chance of spread (in some cases essentially zero). Nevertheless, a pathologist cannot, strictly speaking, label a NET as ‘benign’ because there are no pathologic features that can definitively characterize a NET as non-malignant.
NETs are known for their capacity to produce (secrete) hormones. Hormone-producing tumors are called ‘functional’. These hormones can result in various clinical syndromes. The most common is carcinoid syndrome, which typically occurs in patients with metastatic small bowel NETs, particularly when tumors have spread to the liver. Carcinoid syndrome is caused by production of serotonin and other vasoactive substances. Serotonin is often measured in the urine as 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin. Carcinoid syndrome is characterized by flushing (redness/warmth in the face and neck) and diarrhea. Over time, carcinoid syndrome can result in damage to heart valves, a condition known as ‘carcinoid heart disease’.
Other hormonal syndromes are associated particularly with pancreatic NETs. Insulinomas are pancreatic NETs that produce insulin, a hormone that causes hypoglycemia (low blood sugar). Insulinomas are typically detected early and cured surgically. Gastrinomas usually originate in the pancreas or duodenum, and produce gastrin, a hormone that causes excess acid secretion in the stomach. This leads to ulcers, heartburn, and diarrhea. Other very rare pancreatic NETs include VIPomas which produce vasoactive intestinal peptide, a hormone that leads to extreme watery diarrhea, and glucagonomas which produce glucagon, a hormone that causes weight loss, diabetes, and an unusual rash.
NETs of the adrenal medulla are called pheochromocytomas. They often produce hormones like adrenalin (epinephrine) which cause severe hypertension, palpitations, headaches, and panic attack like symptoms. Pheochromocytomas rarely metastasize. Similar tumors arising in nervous plexuses are called paragangliomas. Most pheochromocytomas and paragangliomas have very low malignant potential and can be cured surgically.
Sometimes, NETs can be discovered after patients present with hormonal symptoms, such as those described above. Most NETs are not hormone producing (nonfunctional) and are discovered either from symptoms of tumor growth, or incidentally (by accident). Tumor-related symptoms depend on location of tumors. For example, NETs of the small intestine can cause chronic intermittent abdominal pain, or even bowel obstruction. Pancreatic NETs can cause jaundice from blockage of bile ducts, or upper abdominal pain and weight loss. Lung NETs can cause cough, sometimes with bloody sputum. Most metastatic NETs spread to the liver, and can cause pain in the right upper abdomen, fatigue and weight loss.
NETs that are found incidentally (during colonoscopy, for example, or scans done for other purposes) are often small and localized.
Most NETs are sporadic (non-hereditary), but a small minority are inherited. Multiple endocrine neoplasia type 1 (MEN-1) leads to tumors in the pituitary gland, parathyroid glands, and NETs in the pancreas and duodenum. Pheochromocytomas are often hereditary, and some are associated with multiple endocrine neoplasia type 2 (MEN-2) which is caused by mutation to the RET gene. MEN2 causes pheochromocytomas, medullary thyroid cancers, and parathyroid tumors.
NETs originating in the small intestine (usually ileum) are often relatively slow growing but have a very high malignant potential (they almost always spread to local lymph nodes or other organs). They tend to metastasize to mesentery (tissue surrounding the intestines) and liver. They frequently produce hormones, including serotonin, which results in the carcinoid syndrome (see above). Tumors in the small intestine or mesentery can cause pain or bowel obstruction (blockage).
There are 3 types of stomach NETs. The most common (type 1) arise from a condition called atrophic gastritis, an autoimmune disease which destroys the acid-producing cells of the stomach. The body responds by producing gastrin, which leads to proliferation of neuroendocrine cells in the stomach and multiple small stomach NETs. These usually have a very low risk of spread. Type 2 stomach NETs arise in patients with gastrinomas (see above) and are very rare. Type 3 are sporadic (not associated with another condition) and tend to be more malignant than the first two types. It also appears that long-term use of acid blocking medications (such as omeprazole) can very rarely lead to NETs in the stomach.
Appendiceal NETs are almost always found incidentally (by accident) during appendectomy for appendicitis or other reasons. If they are under 2cm in size, they almost never spread to other organs.
Rectal NETs are often found incidentally during colonoscopy. If they are small (<1cm), superficial and low-grade, they very rarely behave in a malignant fashion, and can usually be treated by a gastroenterologist without surgery. Rectal NETs are not associated with a hormonal syndrome.
Pancreatic NETs can range from very indolent to highly aggressive. About 10-20% cause hormonal syndromes, the most common being insulinoma syndrome (hypoglycemia). Increasingly, small low-grade pancreatic NETs are discovered incidentally during scans performed for other reasons. Tumors that are smaller than 2cm and low-grade can sometimes be safely observed without surgery.
Lung NETs can be discovered because of symptoms (e.g., cough, shortness of breath or bloody sputum) or incidentally. Low-grade lung NETs are also known as ‘typical carcinoids’ and are rarely malignant in behavior. Intermediate-grade tumors are known as atypical carcinoids. Lung NETs are rarely associated with hormonal syndromes but can sometimes cause carcinoid syndrome or Cushing’s syndrome.
Poorly differentiated NEC are highly aggressive cancers that can originate in many different organs, including the lung, gastrointestinal tract, prostate and cervix. NECs can be composed of small cells (small cell carcinoma) or large cells. Small cell lung cancer is an aggressive neuroendocrine cancer that is usually managed by lung cancer specialists.
NECs are usually metastatic at diagnosis, but even if they are found at a local stage, they have a high potential to metastasize. The treatment of localized NECs can consist of a combination of surgery, radiation, and chemotherapy: typically, at least two modalities of treatment.
Endoscopies (colonoscopies, EGDs) are usually performed by gastroenterologists using a camera to evaluate the upper and lower intestines. Biopsies can be performed when tumors are visualized this way. Endoscopic ultrasound (EUS) can be used to evaluate and biopsy pancreatic tumors, and to better characterize tumors in the stomach, duodenum or rectum. Bronchoscopies are performed by pulmonologists to evaluate the airways (bronchi) and can be used to diagnose lung NETs.
CT scans or MRIs are typical radiographic scans used to evaluate different parts of the body. For evaluating tumors in the liver or pancreas, multiphase or 3-phase CT scans are typically preferred to conventional contrasted CTs.
PET scans use a radioactive isotope to detect tumors. Conventional PET scans use FDG, a radioactive glucose isotope, to detect metabolically active tumors. While this can be useful for some NETs (particularly poorly differentiated and/or high grade), most well-differentiated NETs will not be well-visualized with a standard PET. Instead, special PET scans that image somatostatin receptors are used. These include 68-Gallium-Dotatate PET (Netspot), and 64-Copper-Dotatate PET (Detectnet).
Other diagnostic blood or urine tests are performed to evaluate hormone production and are ordered based on the presence of a clinical syndrome. For example, in patients with suspected carcinoid syndrome (flushing, diarrhea), a blood serotonin or a blood or 24-hour urine 5-HIAA test should be performed. These tests are usually more accurate with avoidance of certain foods before and during the test.
There are certain tumor makers that can be used to evaluate NETs and can correlate with progression or response of disease. The most common one is chromogranin A (CgA). Others include pancreastatin, pancreatic polypeptide or neuron specific enolase (NSE). The benefit of these tests has been increasingly questioned in recent years.
Definitive diagnosis of NET requires evaluation of tumor tissue, either through a biopsy or through surgical resection. Biopsies can be performed endoscopically, or through the skin using image guidance (CT or ultrasound).
Localized NETs that haven’t spread beyond local lymph nodes are often treated with surgery. Some small, superficial NETs (e.g., type 1 gastric NETs or rectal NETs) are managed by gastroenterologists using endoscopic resection techniques.
Tumors that have spread to other organs through the blood or lymphatic system are called metastatic (stage IV).
Well-differentiated metastatic NETs can sometimes be managed surgically, even if all tumors cannot be removed by the surgeon. Such non-curative surgery is called ‘cytoreductive’ or ‘debulking’ surgery.
Neuroendocrine tumors often express somatostatin receptors on their cell surface. Drugs called somatostatin analogs attach to these receptors and can both inhibit tumor growth as well as decrease hormone production in patients with hormonally active (functional) tumors. The two somatostatin analogs commonly used are octreotide (sandostatin) and lanreotide (somatuline). These drugs are typically injected once every 4 weeks in the buttocks. While generally well-tolerated, they can cause side effects such as malabsorption of fatty foods and gallstones.
Since NETs often metastasize to the liver, various liver-directed therapies can be used. Small numbers of tumors can be ablated using radiofrequency or microwave ablation via a probe inserted through the skin or treated with stereotactic radiation. Larger number of tumors can be treated with hepatic arterial embolization using microparticles that are infused into the liver arteries to block the blood supply to the tumors. Hepatic arteries are usually accessed through a catheter inserted in the groin. Embolization can be performed with microparticles alone (bland embolization), mixed with chemotherapy (chemoembolization) or radioactive particles using Yttrium-90 (radioembolization). Embolization often causes pain in the right upper abdomen, nausea, fever, and fatigue. Most symptoms tend to resolve within a week; serious complications such as abscess or liver dysfunction are rare.
Everolimus (afinitor) is a pill that blocks an intracellular enzyme called mTOR. Afinitor is approved for metastatic gastrointestinal, lung and pancreatic NETs. It rarely shrinks tumors but can stabilize disease in many cases. Afinitor can cause side effects such as mouth sores, high blood sugar, lung inflammation, rash, diarrhea, and increased risk of infection.
Sunitinib (sutent) is a pill that blocks receptors on the cancer cell surface, including receptors that contribute to blood vessel growth in tumors (angiogenesis). Sutent is approved for metastatic pancreatic NETs. It rarely shrinks tumors but can stabilize disease in many cases. Sutent can cause side effects such as hypertension (high blood pressure), slightly increased risk of cardiovascular events, and painful rash on the palms and soles.
Chemotherapy drugs target DNA replication. While relatively ineffective for small bowel NETs, certain chemotherapy drugs are quite effective for metastatic pancreatic NETs. One regimen, capecitabine (xeloda) and temozolomide (temodar), is a combination of two oral chemotherapy drugs. This regimen can significantly shrink pancreatic NET tumors in about half of cases. Side effects include fatigue, nausea, and low blood counts which can increase risk of bleeding or infection. Nausea can be prevented in many cases with use of a nausea medication ondansetron (zofran) before temodar.
Peptide receptor radiotherapy (PRRT) refers to drugs that attach a radioactive isotope to somatostatin analog to deliver radiation to NETs that express somatostatin receptors. 177-Lutetium-Dotatate (Lutathera) is approved for metastatic gastrointestinal and pancreatic NETs that have progressed after treatment with somatostatin analogs. The main side effects of this drug are low blood counts. Myelodysplastic syndrome (MDS) or leukemia can occur in about 2-3% of patients treated with Lutathera. There are also concerns about bowel obstruction in patients with extensive disease in the abdomen.
Metastatic poorly differentiated NEC are typically treated with intravenous chemotherapy drugs: cisplatin or carboplatin with etoposide. Although response rates (tumor shrinkage) are quite high, disease tends to relapse quickly. There are no proven second line treatments, although immunotherapy drugs can very rarely result in dramatic responses.
Clinical trials are used to test new drugs or compare efficacy and risks of existing drugs. Participation is clinical trials can both help provide patients with access to new drugs and help to advance the state of knowledge on NET treatments.
