About neuroendocrine tumors (NETs)

What are neuroendocrine tumors (NETs)?

Neuroendocrine tumors, or NETs, are a type of cancer. One way that NETs are different from other types of cancer is that they aren't associated with one specific area or organ, such as breast, lung, or colon cancer. NETs can arise in different tissues and organs throughout the body that contain neuroendocrine cells.

Neuroendocrine cells are found in the nervous system and the endocrine system. These 2 systems work together to keep your body functioning regularly.

The nervous system carries messages from your brain that control various body functions. Some of these messages are sent to the glands of the endocrine system. These glands include the pancreas, hypothalamus, thyroid and parathyroid glands, thymus, pituitary gland, adrenal glands, ovaries, and testes.

Major glands of the neuroendocrine system

Figure reprinted from the Merck Manuals Online Library.

The glands of the endocrine system release hormones. Hormones communicate with specific cells in your body that are involved in important body functions, such as growth, metabolism, reproduction, and response to stress or injury. Some neuroendocrine tumors also have the potential to secrete hormones. These secreting hormones can cause symptoms and conditions including diabetes, flushing, and diarrhea. This is another characteristic of NETs that makes them unique among cancers.

Like other types of cells in your body, neuroendocrine cells can sometimes grow out of control or develop into cancer. This can lead to serious medical conditions, including neuroendocrine tumors.

What are some of the characteristics of NETs?

There is no one type of neuroendocrine tumor: various types of NETs can appear and grow differently and affect patients in different ways.

Although NETs vary in size and how quickly they grow, almost all NETs are considered to be malignant.

• Malignant tumor cells are considered to be cancer. Malignant tumors can grow uncontrollably and spread, or metastasize, to other parts of the body.
• Benign tumors grow slowly or do not grow at all, and they do not spread to other parts of the body. In some NETs cases the tumors will be considered benign.

NETs can metastasize to other parts of the body, most often to the liver or bone.

In fact, by the time they are diagnosed, more than 50% of NETs have already spread to other parts of the body.There are 3 main reasons for this delay in diagnosis:

1. Some NETs are hard to find until they have grown larger or spread
2. Some NETs don't cause symptoms such as low blood pressure, diabetes, or pain, until they have grown or spread
3. Some NETs cause symptoms that are similar to those caused by more common conditions, so it may take longer for a NET to be diagnosed. Most notably, due to the diarrhea associated with carcinoid syndrome, NETs are often misdiagnosed as IBS, irritable bowel syndrome, Diabetes can also be caused by a type of NET that occurs in the pancreas.

Some NETs, however, may be found during routine exams and diagnosed at an early stage of disease.

• Next: Where do NETs occur?

Where do neuroendocrine tumors (NETs) occur?

Many NETs first appear in your gastrointestinal (GI) tract, also called the digestive system. This includes the stomach, duodenum, appendix, and small and large intestine. NETs can also appear in your pancreas, lungs, thymus, and other glands.

The site of origin, also referred to as the primary tumor, is one of the ways that doctors classify NETs. Your doctor may also use terms such as "GI NET," "pancreatic NET," or "lung NET" to describe your tumor. Your doctor may also describe your NET as originating in the "foregut," "midgut," or "hindgut."

Areas in your body where NETs may appear

What are other ways that NETs are classified?

Along with site of origin, there are other ways that doctors describe and categorize NETs.

Your doctor may talk about your NET in terms of whether it does or does not secrete hormones. Hormone secretion is a common characteristic of some types of NETs.

• NETs that secrete hormones are called "functional" tumors
  • If a NET secretes large amounts of hormones, it may cause a variety of symptoms
• NETs that don't produce hormones are called "nonfunctional" tumors
  • These NETs may only cause symptoms due to the tumor's growth, such as pain, intestinal blockage, or bleeding

Doctors also classify NETs in terms of what they look like under a microscope (how they are structured). This includes how differentiated a NET is from the surrounding tissue.

A NET may be described as being "well" or "poorly" differentiated.

• Well-differentiated NETs can be low or intermediate grade. Low-grade NETs generally grow slowly. Intermediate-grade NETs are more variable in how they grow.
  • Well-differentiated NETs appearing in parts of the digestive system and lungs traditionally have been called "carcinoids" However, your doctor may use the term "carcinoid" to describe all types of NETs. Be sure to ask your doctor to clarify the terms he or she is using.
• Poorly differentiated NETs are high grade. They generally are aggressive, and grow and spread rapidly

These factors – where your NET is located, the hormones it secretes (if any), how far it has spread (if at all), and how aggressive the tumor is (how fast it may continue to grow or spread) – can help your doctor develop a management plan for you.

• Next: What symptoms are associated with neuroendocrine tumors?
• Previous: What are neuroendocrine tumors?

What symptoms are associated with
neuroendocrine tumors (NETs)?

Different types of NETs cause different symptoms. The symptoms you may experience depend on whether or not your NET is functional or nonfunctional, and on the location of the tumor.

• Functional NETs produce symptoms caused by the secretion of hormones and other substances
• Nonfunctional NETs do not secrete hormones. They may only produce symptoms caused by the tumor's growth, such as intestinal blockage, pain, and bleeding

Some NETs are named based on the hormones they secrete. These names include "gastrinoma" (gastrin), "glucagonoma" (glucagon), and "insulinoma" (insulin), and there are several others. NETs also are sometimes referred to as "carcinoids." Your doctor may use one of these terms when talking to you about your tumor.

The hormones and other products secreted by functional NETs sometimes cause clinical syndromes. A syndrome is a set of symptoms that occur together due to the presence of a disease.

The syndrome caused by a functional NET depends on the hormones it secretes. Some key types of functional NETs and the syndromes they may cause are shown in the accompanying table.

Syndromes and symptoms that may be caused by functional NETs

Type of NET	Typical location	Hormone produced	Associated syndrome	Characteristic symptoms*
Carcinoid (well-differentiated NET)	Stomach, bowel, small intestine, pancreas	Serotonin	Carcinoid syndrome	Diarrhea (including nighttime) Flushing Cramping Wheezing Pellagra (causes abdominal pain; redness and swelling of the mouth and tongue; skin rash; and memory loss) May also cause lesions in the heart valves
Gastrinoma	Duodenum, pancreas	Gastrin	Zollinger-Ellison syndrome	Ulcers Diarrhea
Insulinoma	Pancreas	Insulin	Hypoglycemia syndrome (Whipple's triad)	Hypoglycemia Weight gain Poor or abnormal absorption of nutrients Insulin resistance
VIPoma (vasoactive intestinal peptide tumor)	Pancreas	Vasoactive intestinal peptide (VIP)	Verner-Morrison syndrome	Watery diarrhea (also known as pancreatic cholera), which can cause hypokalemia or hypochlorhydria
Glucagonoma	Pancreas	Glucagon	—	Rash Glucose intolerance (diabetes) Weight loss
Somatostatinoma	Pancreas, duodenum	Somatostatin	—	Hyperglycemia Diarrhea (bulky, greasy, odorous) Hypochlorhydria Weight loss
ACTHoma	Pancreas	Adrenocorticotropic hormone ACTH	Cushing's syndrome	Excessive torso fat Large, round face Muscle fatigue Thin skin
GRFoma	Pancreas	Growth hormone releasing factor GRF	Acromegaly	Bone deformity Heart failure Weakness Vision problems

A closer look at carcinoid syndrome

Carcinoid syndrome occurs in some patients with NETs. It is associated with the secretion of a hormone called serotonin and other biochemicals by the tumor.

The symptoms of carcinoid syndrome usually become more noticeable when the NET starts to grow or spread. This group of symptoms includes:

• Turning red and feeling warm in the face or neck (called "flushing"), which usually occurs without sweating. This kind of flushing is different from menopausal flushing that usually comes with sweating.
• Diarrhea, can often occur at night, which is a clue that differentiates NETs from IBS, irritable bowel syndrome.
• Abdominal pain

It is important to remember that these symptoms are similar to those caused by other digestive system disorders, such as irritable bowel syndrome (IBS). This can make carcinoid syndrome difficult to diagnose, even for experienced doctors.

Other symptoms and signs of carcinoid syndrome include:

• Wheezing
• Rapid heart rate or palpitations
• Skin lesions or discolored patches of skin

A closer look at pancreatic NETs

Other types of NETs occur in the pancreas. They are known as pancreatic NETs. They can secrete different kind of hormones that can cause a variety of symptoms. Click here to find out more information about pancreatic NETs and the symptoms associated with them.

However, not all pancreatic NETs are associated with secretion of hormone products related to clinical symptoms.

Pancreatic NETs are different than other types of pancreatic cancers. They account for only 1% of all pancreatic cancers. They also tend to be less aggressive than other types of cancers found in the pancreas, and patients may generally have a better outlook.

Remember, however, that most pancreatic NETs are considered to be malignant tumors. So it is important to keep your doctor informed about all the symptoms you are experiencing, even if you don't think they are related to your NET.

A closer look at bronchial NETs

In addition to the pancreas, NETs can also originate in the bronchial system. This includes the lungs and thymus. Patients with bronchial NETs may experience asthma-like symptoms, such as coughing and wheezing.

Bronchial NETs vary in how aggressively they grow. Patients generally have a better outlook than patients with other types of lung cancers.

Remember, however, that most bronchial NETs are considered to be malignant tumors. So it is important to keep your doctor informed about all the symptoms you are experiencing, even if you don't think they are related to your NET.

• Next: What tests are used to diagnose and monitor NETs?
• Previous: Where do neuroendocrine tumors occur?

What tests are used for neuroendocrine tumors (NETs)?

A number of tests are commonly used to help identify or confirm the presence of a NET, and to track any changes in your NET that might occur over time. In some cases, tests can also be used to see how you are responding to treatment.

These tests include imaging and biochemical tests. Your doctor may conduct some of them, or you may be referred to a specialist for others. Your doctor will determine which tests are appropriate for you and how often you need them.

Imaging tests

How are these imaging tests different?

MRI is usually used for imaging soft tissue, while CT is the preferred technique for imaging bone. CT and Octreoscan use a radiation source, while MRI does not.

Biochemical tests

It is important to note that results of biochemical tests are preliminary. Your doctor should confirm the results with other types of tests, such as imaging and microscopic analysis of cells and tissue.

It is important to keep accurate records about any tests you've had scheduled and the results of the tests. Also, ask your doctor about any changes in your test results and what they mean. Record your doctor's answers.

Octreoscan is a trademark of Covidien AG or one of its affiliates.

• Next: How are neuroendocrine tumors managed?
• Previous: What symptoms are associated with neuroendocrine tumors?

How are neuroendocrine tumors (NETs) managed?

It is also important to remember that NETs sometimes do not spread or cause symptoms for long periods of time. Because of this, your doctor may recommend a gradual period during which your disease is observed.

Your doctor may suggest this strategy, at least initially, if your NET is causing occasional symptoms that can be controlled with diet and lifestyle adjustments, or if the risk of surgical or medical intervention outweighs the benefit. During this time, your doctor may continue to order tests to monitor your disease.

Are other treatment options being tested or developed?

Clinical studies are being conducted to evaluate new methods for managing NETs or new ways of using available methods.

You can learn more about clinical studies involving NETs on ClinicalTrials.gov (www.clinicaltrials.gov), a Web site that lists all clinical studies currently being conducted throughout the world. The site gives you information about a study's purpose, who may participate, locations, and phone numbers for more details. This information should only be used in conjunction with advice from your doctor.

Your doctor will work with other members of your healthcare team to determine the best management plan for you. It may be important to be referred to a NET expert, who has access to the appropriate management options.

• Previous: What tests are used for NETs?