What Are Neuroendocrine Tumors (NETs)?

Neuroendocrine tumors (NETs) are considered rare tumors that originate in specialized cells called neuroendocrine cells. Neuroendocrine cells are nerve cells (neurons) that can conduct nerve impulses and also make hormones.

A hormone (sometimes called a chemical messenger) is a chemical that is usually produced by endocrine glands and released into the bloodstream to send messages to other parts of the body. Endocrine glands include the pancreas, thyroid, pituitary, and adrenal glands.

Neuroendocrine tumors receive signals from the nervous system and respond by making hormones and releasing them into the blood. The signals control many different functions in the body.

Because NETs are comprised of cells that produce hormones, the tumors are also capable of producing hormones. When NETs metastasize (spread to other areas of the body) it can result in hormonal imbalances that can cause unwanted symptoms.

Other names for neuroendocrine tumors are “neuroendocrine neoplasia,” and “neuroendocrine neoplasm.”

Anatomical Features

Neuroendocrine tumors are referred to as epithelial neoplasms (abnormal growth of cells arising from and composed of epithelial cells in the body). Epithelial cells are a type of cell that lines the surfaces of the body, such as blood vessels and organs.

Neuroendocrine cells are comprised of epithelial cells because they come from places made up of epithelial cells such as in the lining of the airways. Scattered neuroendocrine neoplasms can be found singly or in small nests.

Neuroendocrine cells function differently depending on where they are located in the body. Neuroendocrine cells produce hormones that do things such as controlling the growth and development of a young person, influencing how the body responds to stress, and more.

When mutations occur in neuroendocrine cells, the cells begin to grow out of control, forming neuroendocrine tumors.

neuroendocrine tumor ribbon
Chinnapong / Getty Images

Types of Neuroendocrine Tumors

There are many different types of neuroendocrine tumors; the precise type of NET depends on where —in the body—the tumor originated.  Traditionally, neuroendocrine tumors have been referred to as “carcinoids,” but this term does not accurately describe the various differences between types of NETs.

Neuroendocrine tumors can be broken down into two basic categories, including nonfunctional and functional NETs, the difference is:

  • Functional neuroendocrine tumors result in a specific set of symptoms (due to the production of excess hormones)
  • Nonfunctional neuroendocrine tumors do not usually cause specific symptoms

Further classification of neuroendocrine tumors breaks the tumors down into a few types, including:

  • Carcinoid tumors: This type arises in the lungs, appendix, thymus, or digestive tract. They can also grow in the brain, bone, skin, lymph nodes, testes, and ovaries. Carcinoid tumors can arise from the pancreas (but this is rare).
  • Pancreatic neuroendocrine tumors are sometimes referred to as islet cell tumors. These occur in the pancreas, and sometimes outside of that organ.
  • Pheochromocytoma: This is a rarer type of neuroendocrine tumor that usually arises in the adrenal gland (but can grow in other parts of the body as well).

Other subtypes of NETs include:

  • Gastroenteropancreatic neuroendocrine tumor
  • Hereditary paraganglioma-pheochromocytoma
  • Merkel cell carcinoma
  • Paragangliomas

Where Neuroendocrine Tumors Are Found

Neuroendocrine tumors can develop in the body, anywhere. However, most are found in the gastrointestinal tract (digestive tract), pancreas, lungs, rectum, or appendix. They can be benign (non-cancerous) or malignant (cancerous). Usually the grow very slowly over time, but some forms of NETs are rapid-growing.

According to the Cancer Research Center, approximately 5 out of every 10 (50%) neuroendocrine tumors arise from the digestive system, and approximately 2 out of every 10 (20%) neuroendocrine tumors (20%) begin in the lung.

The tumors are named for the area they arise in, for example, a tumor that arises in the lungs is called a lung NET. The lung NET would be considered the primary cancer. If the NET spreads (metastasizes) to another part of the body, it would be considered a secondary tumor.

Areas that primary NETs are commonly found include:

  • Stomach
  • Small and large intestine
  • Pancreas
  • Rectum
  • Lung
  • Esophagus (the food pipe)
  • Appendix
  • Skin
  • Prostate
  • Uterus (womb)
  • Pituitary gland
  • Adrenal gland
  • Parathyroid gland

Sometimes, the diagnostician is unable to determine where the neuroendocrine tumor originated; this is referred to as cancer of unknown primary (CUP).

Neuroendocrine Tumor Symptoms

Most NETs are slow to develop and may take years before symptoms are noted and NETs are detected. The symptoms of a NET can vary, depending on several factors, such as the size and location of the tumor, the type of tumor (referring to where in the body the tumor originated), and whether or not the tumor has metastasized.

In many cases of neuroendocrine tumors, there are no symptoms until the tumor/s begin to metastasize or the NETs begin to impair an organ (such as the liver) or a body system (such as the digestive system).  Because there are generally no symptoms early on, NETs can be very difficult to diagnose.

Causes

The actual cause of neuroendocrine tumors is widely unknown. Scientists are doing research to attempt to discover the causes of neuroendocrine tumors.

According to the National Center for Advancing Translation Sciences, most neuroendocrine tumors are not linked with hereditary factors. They tend to occur very sporadically in those without a family history of NETs.

Associated Conditions

Although neuroendocrine tumors are not considered hereditary, in some cases, some of the risks of getting the tumors can be passed down from another family member. Some types of neuroendocrine tumors are associated with an autosomal dominant inherited cancer or tumor syndrome, such as:

  • Multiple endocrine neoplasia type 1: This is an inherited condition that causes tumors of the endocrine system.
  • Von Hippel-Lindau disease: This is an inherited condition that can cause cancerous growths in many parts of the body.
  • Tuberous sclerosis: This is a genetic condition characterized by the growth of benign (non-cancerous) tumors throughout the body, including the brain, kidneys and heart.
  • Neurofibromatosis type 1: This is a genetic condition that affects the skin, the bones, and the part of the nervous system, involving benign growths along the nerves.

Genetic testing may be necessary for people who have been diagnosed with NETs. The primary goal of testing would be to look for inherited conditions or syndromes that can increase a person’s risk for neuroendocrine tumors.

If you have an inherited risk, such as a family history of specific types of syndromes, your healthcare provider may order genetic testing.

Risk Factors

Factors that may increase a person’s risk of developing NETs include:

  • Inherited syndromes (as listed above)
  • Race: Neuroendocrine tumors are more common among white people than among Black people.
  • Ethnicity
  • Gender: Neuroendocrine tumors are slightly more common in women than in men.
  • Age
  • Environment
  • Diet

Treatment

The specific type of treatment recommended for neuroendocrine tumors can depend on many different factors, including:

  • The size of the tumor(s)
  • The location of the tumor(s)
  • Whether the tumor(s) have metastasized
  • The type of tumor (where, in the body, it originated from)
  • The aggressiveness of the tumor(s)
  • Any hormone producing properties
  • Other factors (such as a person's general health condition)

Surgery for NETs

Surgery to remove the tumor is the most common type of treatment for NETs. This type of surgery requires the skill of a specialist called a surgical oncologist. Most NETs are treated very successfully with surgery alone.

However, if surgery is not successful, there are several other types of management options available, including non-surgical therapies (to shrink the tumor, stop it from growing or manage symptoms).

Carcinoid Crisis

Those who have carcinoid syndrome have a high risk of developing carcinoid crisis  (a rare disorder that involves rapid heartbeat, trouble breathing, and more) during surgery. A fully trained team of anesthesiologists must be available (and be aware of the risks) in case carcinoid crisis occurs. A medication called octreotide (administered via intravenous therapy) should be given before surgery to prevent carcinoid crisis.

Treatment Team

If you have been diagnosed with neuroendocrine cancer, there may be several different types of healthcare providers on your treatment team if you’ve been diagnosed with neuroendocrine tumors. Your care team may include:

  • A surgical oncologist: A surgeon who specializes in the treatment of cancer
  • An endocrinologist: A medical doctor, specializing in treating conditions of the endocrine system
  • A radiation oncologist: A medical doctor trained in administering radiation for cancer treatment
  • A gastroenterologist: A medical doctor who specializes in the treatment of conditions of the gastrointestinal (digestive) tract
  • A nuclear medicine physician: A physician who uses radioactive materials, called radiopharmaceuticals, to diagnose and treat disease

In addition to special types of doctors to treat your neuroendocrine tumor, your multi-disciplinary care team may be comprised of other healthcare providers, such as:

  • A dietitian
  • An oncology nurse (specially trained to care for cancer patients)
  • A nurse specialist
  • A mental health counselor

Health Insurance and Advocacy

Because there are many types of specialty care for the treatment of NETs, you may run into some problems with denial of claims, depending on the type of health insurance coverage you have.

Coverage

If you plan to be treated at a specialty clinic, such as being seen at a neuroendocrine tumor center, you may get denied by your health maintenance organization (HMO) or other insurance plan for out-of-network surgery.

But, according to the Carcinoid Cancer Foundation, most insurers claim that if they cannot provide a specific type of provider (worded in the coverage contract as “a qualified medical professional for your specific condition”) they will authorize a consultation with an out-of-network provider.

Some insurance plans will even cover services that are out of state. The trick is to read your coverage contract. If your healthcare plan was purchased through your employer, be sure to ask for a copy of your coverage contact through your job.

Getting Your Treatment Covered by Insurance

According to founding board member, Julie Portelli, at the Carcinoid Cancer Center, when you’ve been denied for medical treatment or for seeing an out-of-network specialist for your neuroendocrine cancer, “Don't give up—now you have to prove to your insurance company where in their contract it calls for the service or treatment you are requesting.”

One such treatment that commonly gets denied for payment by many insurance providers is peptide receptor radionuclide therapy (PRRT). You can learn more about the legalities of filing a claim with your insurance company for specialty treatment modalities ordered by your healthcare provider from PRRTinfo.org.

According to PRRT.org, some insurance companies are known to cover PRRT. These include:

  • Aetna (partial coverage)
  • Nationwide Better Health
  • Cigna (self-funded and Medicare Advantage)
  • United Healthcare (self-funded)
  • Blue Shield of CA
  • Blue Cross / Blue Shield of the following states: Michigan, Minnesota, Nebraska, Iowa, Illinois, Pennsylvania, Texas

Don't automatically assume that because you have one of the plans on the list that your PRRT will be covered. Insurance plans can differ from region to region in the same state. Also, coverage doesn't always stay the same, so be sure to refer to your coverage contract to be sure that you are covered.

Portelli says to be sure to pursue a legal appeal process. The Northern California CarciNET Community has her further advice on the steps to file for an authorization to see a medical provider or visit a center that is out of network here.

Another resource to use to learn more about the legal process of filing an appeal for denied insurance claims is the Cancer Legal Resource Center.

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Article Sources
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  1. Canadian Cancer Society. The neuroendocrine system.

  2. National Center for Advancing Translation Sciences. Neuroendocrine tumor. Updated April 25, 2019.

  3. Centers for Disease Control and Prevention (CDC). Malignant neuroendocrine neoplasms. Updated October 4, 2013.

  4. Canadian Cancer Society. What are neuroendocrine tumours?

  5. Neuroendocrine Tumor Research Foundation. Causes of neuroendocrine tumors.

  6. Neuroendocrine Tumor Research Foundation. Genetic testing for neuroendocrine tumors.

  7. American Society of Clinical Oncology. Neuroendocrine tumor of the gastrointestinal tract: Risk factors. Updated October, 2019.

  8. American Society of Clinical Oncology. Neuroendocrine tumors: Types of treatment.Updated April 2019

  9. The Carcinoid Cancer Foundation. Resources for carcinoid and NET cancer insurance appeals.

  10. PRRTinfo.org. Working with your insurance.