Neuroendocrine Tumors

About

Dr. Deepak Chhabra

Surgical Oncologist

MS. (Bom), DNB, M.R.C.S. (Edin. UK)

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The world knows this man as a consultant oncosurgeon with vast experience in Gastrointestinal and Hepatobiliary-Pancreatic cancers,who specializes in stapled anastomosis for bowel cancers and sphincter saving resections for rectal cancers. In short, he is the person to be contacted for all kinds of cancer related cases.

Richa AgrawalPancreatic Cancer

Thank you Dr Deepak for all you have done for mum, for putting the smile back of her face. I wish you success in all your future endeavors and know that you will continue to touch peoples lives and help them be healthy - the way you have done for my mum….. and me.

Nicola MathiasStomach Cancer

For 67years I've led a very healthy life and thank the "Almighty" for it. However as I said all good things come to an end some time and so be it. Out of the blues was detected the dreadful illness "C" which had shown no signs or symptoms whatsoever..... Time had now come for me to choose a very efficient Oncologist for my treatment.

Patient

My mother was diagnosed of colon cancer, and I was recommended to see Dr Deepak Chhabra for consultation.
The first impression of Dr Chhabra was… he is so young! But after consulting him we realized his level of experience and there was a sense of confidence he spilt over us.We knew we could trust him.....

Neelu GroverColon Cancer
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What is a neuroendocrine tumor?

The diffuse neuroendocrine system

Our body has some different types of cells that behave like nerve cells in certain ways and like hormone-making endocrine cells in other ways. These cells do not form an actual organ, instead, they are scattered throughout other organs like the oesophagus, stomach, pancreas, intestines, and lungs. The digestive system is large and contains more neuroendocrine cells than any other part of the body.

Neuroendocrine cells help control the release of digestive juices and how fast food moves in the GI tract. They may also help control the growth of other types of digestive system cells.

About

Neuroendocrine tumors

Like most cells in the body, GI tract neuroendocrine cells sometimes go through certain changes that cause them to grow too much and form tumors. These tumors are known as neuroendocrine tumors (NET) and neuroendocrine cancers. In the past, most abnormal growths of neuroendocrine cells were called carcinoids. But in 2000, the World Health Organization (WHO) reclassified carcinoids into neuroendocrine tumors and neuroendocrine cancers.

Neuroendocrine tumors are growths that look benign (i.e not cancerous) but that might possibly be able to spread to other parts of the body. Neuroendocrine cancers are abnormal growths of neuroendocrine cells which can spread to other parts of the body.

Neuroendocrine cancers (also known as neuroendocrine carcinomas) can then be divided into groups based on the way the cells look under the microscope. A cancer with cells that do not look very abnormal is called well differentiated. These tumors tend to be less aggressive. They grow and spread slowly. Well differentiated neuroendocrine cancers can look identical to benign neuroendocrine tumors when examined under the microscope. Sometimes the only way to know for certain that a mass is a neuroendocrine cancer (and not a benign tumor) is when it spreads to other organs or tissues. If the cells of a cancer look very abnormal, it is called poorly differentiated. These cancers tend to be more aggressive meaning that they grow and spread quickly.

Neuroendocrine tumors can be classified as functional and non-functional.

Neuroendocrine tumors and cancers act like the cells they come from, often releasing certain hormone-like substances into the bloodstream. These excess hormones are responsible for producing symptoms. As example of this is that a tumor in the pancreas may produce a hormone called insulin. This hormone is normally responsible for keeping the blood sugar levels under control. An excess of this hormone can cause a drastically low blood sugar levels and a person may have repeated fainting episodes. Such a tumor is then named after its hormone producing substance viz Insulinoma. This is then labelled as a functional tumor. A Gastrinoma is responsible for producing gastrin, that secretes excess of stomach juice and is responsible for severe acidity.

In contrast; non-functional tumors do not produce hormones. These tumors can go undetected for a long time and may come to notice once they have attained a large size and are often found incidentally during investigations for some other reason.

In general, neuroendocrine tumors and neuroendocrine cancers grow more slowly than other cancers in the GI tract. But how they grow and whether or not they spread to other areas varies widely. This depends to some extent on which part of the body the tumor starts in.

Causes

What are the risk factors for gastrointestinal carcinoid tumors?

A risk factor is anything that affects your chance of getting a disease such as cancer. For example, exposure to strong sunlight is a risk factor for skin cancer, while smoking is a risk factor for cancer of the lung, and several other cancers. But risk factors don’t tell us everything. Someone without any known risk factors can still develop cancer. And someone can have a risk factor, but still not get the disease. Only a few risk factors for neuroendocrine tumors are known, such as:

Genetic syndromes

Multiple endocrine neoplasia, type I: This is a rare condition caused by inherited defects in the gene MEN1. People with this syndrome have a very high risk of getting tumors of 3 glands: the pituitary, parathyroid, and pancreas. They also have an increased risk of carcinoid tumors. Some studies estimate that inherited mutations of the MEN1 gene are responsible for about 10% of carcinoid tumors. Most of these are gastric (stomach) carcinoids. Children have a 50/50 chance of inheriting this syndrome from an affected parent.

Neurofibromatosis type 1: This disease often runs in families and is characterized by many neurofibromas (benign tumors that form in nerves under the skin and in other parts of the body).It is caused by defects in the gene NF1. Some people with this condition also develop neuroendocrine tumors of the small intestines.

Other stomach conditions

People with certain diseases that damage the stomach and reduce the amount of acid it makes have a greater risk of developing stomach carcinoid tumors, but their risk for carcinoid tumors of other organs is not affected.

How are gastrointestinal carcinoid tumors diagnosed?

As mentioned in the last section, gastrointestinal (GI) carcinoids often do not cause any symptoms and may be found when looking for causes of other problems. But some do cause symptoms that may lead to their diagnosis.

Symptoms

What are the common symptoms of neuroendocrine tumor?

Most tumors grow slowly and produce vague symptoms that are more often caused by something else. When trying to figure out what’s going on, doctors and patients are likely to explore other, more common possible causes first. This can delay a diagnosis, sometimes even for several years.

The symptom a person develops from a gastrointestinal neuroendocrine tumor often depends on where it is located. Pancreatic neuroendocrine tumors are most often non-functional and are often detected incidentally. Functional tumors produce hormones and are responsible for symptoms for eg Insulinoma produces insulin and lowers blood sugar levels, Gastrinoma produces gastrin and causes hyperacidity, VIPoma produces a peptite that is reposnsible for severe and oft repeated diarrhoea.

People with tumors/cancers in their appendix often don’t have symptoms. If it is discovered, it is often when they have their appendix removed during an operation for some other problem.

If the tumor/cancer starts in the small intestine, it can sometimes kink or block the intestines, causing abdominal pain. This pain can be mild and last for a couple of years or more before the carcinoid tumor is found. Often a tumor needs to grow fairly large before it blocks (obstructs) the intestine. When that happens, patients have severe abdominal pain, nausea and vomiting.

Sometimes, a tumor may cause intestinal bleeding. This can lead to anaemia (low red blood cell counts) with fatigue and shortness of breath. These same problems can also occur with carcinoid tumors that start in the colon. Rectal carcinoid tumors are often found during routine exams, even though they can cause pain and bleeding from the rectum.

Carcinoid tumors that develop in the stomach usually grow slowly and often do not cause symptoms. They are sometimes found during an exam of the stomach by endoscopy that is done to look for other things. Some can cause symptoms such as the carcinoid syndrome.

Carcinoid syndrome: In about 1 out of 10 cases, carcinoid tumors release enough hormone-like substances into the bloodstream to cause symptoms. This results in the carcinoid syndrome. Symptoms include:

  • Facial flushing (redness and warm feeling)
  • Severe diarrhea
  • Wheezing
  • Fast heartbeat

Tests

What tests are carried out to diagnose pancreatic cancer?

This section lists common tests that may be performed and it is not necessary for all the tests to be performed for a patient. Your doctor will select the tests that will assist him /her to have the maximum information about the tumor/ disease.

Computerised tomography (CT) scan

A CT scan is a type of x-ray that gives a picture of organs and other structures (including any tumours) in your body. It is used to see more details of a cancer and its relation to the surrounding organs in your body. It also gives information related to cancer spread into the lymph nodes, liver or lungs.

CT scans can help tell if your cancer has spread into lymph nodes or other organs such as your liver. They can also be used to guide a biopsy needle precisely into a suspected area of cancer spread. For a CT-guided needle biopsy, the patient remains on the CT scanning table, while a doctor moves a biopsy needle in the body toward the location of the mass. CT scans are repeated until the doctor is sure that the needle is in the mass. A fine-needle biopsy sample (tiny fragment of tissue) or a core-needle biopsy sample (a thin cylinder of tissue about ½-inch long and less than 1/8-inch in diameter) is then removed and looked at under a microscope.

Magnetic resonance imaging (MRI)

This test is like a CT scan, but it uses magnetism instead of x-rays to build up pictures of the organs in your abdomen. Like a CT scan, MRI is painless and the magnetism is harmless. MRI scan may be used to see the extent of blockage of bile duct and in case the patient is allergic to contrast dye injection used for CT scans.

Endoscopic ultrasound (EUS)

This test uses an endoscope with a small ultrasound probe on the end. This probe releases sound waves and then detects the echoes that bounce off tissues of the digestive tract wall. A computer then translates the pattern of echoes into an image of the wall of the esophagus, stomach, intestine, or rectum. Putting the ultrasound probe on the end of an endoscope lets it get very close to the tumor. Because the probe is close to the area being studied, it can make very detailed pictures. EUS can be used to see how deeply a tumor may have grown into the wall of the esophagus, stomach, intestine, or rectum. Endoscopic ultrasound can also help see if certain lymph nodes are enlarged and help a doctor guide a needle into a lymph node, tumor, or other suspicious area to do a biopsy.

Biopsy

Even if an imaging test finds a mass, it cannot tell if the mass is a neuroendocrine tumor, some other type of tumor or cancer, or an area of infection. The only way to know for sure is to remove cells from the abnormal area and look at them under a microscope. This procedure is called a biopsy.

There are several ways to take a sample from a gastrointestinal tumor. One way is through the endoscope. When a tumor is found, the doctor can use a biopsy forceps (pincers or tongs) through the tube to take a small sample of it. Another way to sample a tumor is with a CT-guided needle biopsy, as was described in the section on CT scans.

Radionuclide scans

Scans using small amounts of radioactivity and special cameras may be helpful in looking for neuroendocrine tumors. They can help determine the extent of the tumor, as well as help locate it if doctors aren’t sure where it is in the body.

OCTREOSCAN: Somatostatin receptor scintigraphy, also known as OctreoScan, is the scan most commonly used to look for neuroendocrine tumors. It uses a hormone-like substance called octreotide that has been bound to radioactive indium-111. Octreotide attaches to proteins on the neuroendcorine cells. A small amount of this substance is injected into a vein. It travels through the blood and is attracted to neuroendocrine tumor cells. About 4 hours after the injection, a special camera is used to show where the radioactivity has collected in the body. More scans may be done over the next few days as well.

Positron emission tomography (PET) scan

A positron emission tomography (PET) scan is another imaging test that uses low levels of radioactivity to look for tumors. For most diseases, PET scans use a form of radiolabelled glucose (sugar) to find tumors. But when it is used to look for neuroendocrine tumors/cancers, PET uses a radioactive form of 5-hydroxytryptophan (5-HTP), a chemical that is taken up and used by neuroendocrine cells. A special camera can detect the radioactivity. Some doctors have found PET scans to be more accurate than CT scans for detecting spread of disease. However, this technique is not available in every hospital.

Blood and urine tests

Tests of the blood and urine can be very helpful in diagnosing carcinoid syndrome in patients who have symptoms that may be caused by it.
Serotonin (also called 5-HT) is a substance made by many carcinoid tumors, especially those in the small intestine. It is probably the cause of at least some of the symptoms of carcinoid syndrome. The body breaks it down into 5-hydroxyindoleactic acid (5-HIAA), which is released into the urine. A commonly used test to look for carcinoid syndrome measures the levels of 5-HIAA in a urine sample collected over 24 hours.

Eating foods that contain a lot of serotonin can raise 5-HIAA levels in the urine. Such foods include, bananas, plantains, kiwi, certain nuts, and avocado. Medicines, including cough syrup and acetaminophen (Tylenol), can also affect the results. These substances should be avoided before urine and blood testing for carcinoids.

Other commonly used tests to look for carcinoids can include blood tests for chromogranin A (CgA), and gastrin. Depending on the where the tumor might be located and on the patient’s symptoms, doctors may do other blood tests as well.
Some of these tests can also be used to show how well treatment is working, since the levels of these substances tend to go down as tumors shrink.

Treatment

What is the treatment of pancreatic cancer?

General approach to treatment

The main factors in selecting treatment options for a neuroendocrine tumor are:

  • Its size and location
  • Whether it has spread to lymph nodes, liver, bones, or other organs
  • Whether you have any other serious medical conditions
  • Whether the tumor is causing bothersome symptoms

Surgery

Surgery remains the best option of treatment for Neuroendocrine tumors. Unlike other cancers these tumors tend to grow slowly but occasional tumors can be aggressive as well. Unlike other organ cancers if tumor shows signs of spread (metastases), it can still be treated aggressively by removal or destruction of the tumors. Example a surgeon may not give too much hope for a person with Stomach Cancer that has spread to the liver but a person with neuroendocrine tumor that has spread to the liver will still be treated aggressively and may even get cured.

The options for neuroendocrine tumors that have spread locally or distantly are more complex. Because most neuroendocrine tumors grow very slowly and some do not cause any symptoms, completely removing all metastatic tumors may not always be needed. In some patients, surgery to remove all visible cancer is the best option. This is particularly true if removing most of the cancer will reduce the level of hormone-like substances causing symptoms.

Several types of operations may be used to treat neuroendocrine tumors. Some of these remove the primary tumor (where the cancer started), while others remove or destroy cancer spread (metastases) in other organs such as RFA (radiofrequency ablation).

Several medicines can help control the symptoms of carcinoid syndrome / hormonal symptoms in patients with metastatic neuroendocrine cancers.

Octreotide (Sandostatin®) is an agent chemically related to a natural hormone, somatostatin. It is very helpful in treating flushing, diarrhea, and wheezing from carcinoid syndrome. While this drug rarely shrinks carcinoid tumors, it may slow or stop their growth. Although this is not curative, it can prolong life.

This drug comes in a short-acting version that is given 2 to 4 times a day. It is also available as a long-acting injection that needs to be given only once a month (Sandostatin LAR®), which may help patients more than the short-acting version.. A newer drug, pasireotide, is currently being studied.

Chemotherapy.

Chemotherapy uses anti-cancer drugs that are injected into a vein or a muscle or taken by mouth to kill cancer cells. These drugs enter the bloodstream and reach all areas of the body, making this treatment useful for some types of cancers that have spread to other organs.

Unfortunately, not many neuroendocrine tumors respond to chemotherapy. Because of this, chemotherapy generally is used only for tumors that have spread to other organs, are causing severe symptoms, and have not responded to other medicines. Tumors may be treated with more than one drug, although it’s not clear that this is any more effective than using a single drug. New chemotherapy drugs and combinations of drugs are being studied.

Interferons

Interferons are natural substances that normally activate the body’s immune system. They also slow the growth of tumor cells. Interferon-alfa is sometimes helpful in shrinking or slowing the growth of metastatic neuroendocrine cancers and improving symptoms of carcinoid syndrome. Its usefulness is sometimes limited by its flu-like side effects, which may be severe. The drug is given by injection.

Intra-arterial therapy and chemoembolization.

Normally, chemotherapy drugs enter the bloodstream and can travel throughout the body. When carcinoid cancer has spread to the liver, it is sometimes treated by directly injecting the chemotherapy drug into the hepatic artery, which supplies blood to parts of the liver. This exposes the liver tumors to high doses of the drug but limits exposing the rest of the body. Sometimes the chemotherapy drug is injected together with a material that plugs up the artery (an approach called chemoembolization). When the arteries leading to them are blocked, the tumors become starved for nutrients and oxygen and many die off.

At first, even tiny meals may make you feel uncomfortably full. You will need to eat very small amounts very often at first. Then, gradually increase the amounts and then the time between meals. At first, you may find you need to eat every hour or so in order to get enough nutrition.

There is no restriction on the type of food you eat after a pancreas surgery and you should be able to eat all that you did before surgery. Fizzy drinks can make you feel full – it is probably best not to drink with meals at all, as any liquid will fill you up.

Try keeping a food diary if you are having problems you think are related to your diet. Take a small notebook and draw a line down the centre of each page. Write down what you eat and when on the left of the page. Write down any symptoms you get and when on the other side of the page. After a few days, you may be able to spot which foods cause which symptoms.

Some people need to take tablets to help digest fat and proteins, and some people develop diabetes, which may require treatment.

Several newer types of drugs, known as targeted therapies, are now being studied for use against neuroendocrine tumors and cancers. These drugs are designed to attack some specific aspect of cancer cells. Bevacizumab (Avastin®), for example, attacks a tumor’s blood supply. It is already being used against some types of cancer and is being studied for these tumors. Other targeted therapies block the molecules that increase the growth of cancer cells. Some of these (such as erlotinib, temsirolimus, sorafenib) are used in other types of cancer and are now being tested against carcinoids.

Radionuclide scans, such as the Octreoscan, can be helpful in finding neuroendocrine cancers because they use substances that are attracted to neuroendocrine cells. These substances are attached to slightly radioactive elements so that they can be detected with special cameras. Using higher doses of Octreotide delivers more radiation to the tumor cells and is used in very few centres to treat neuroendocrine tumors and cancers. Doctors are now using octreotide labelled with a radioactive form of the element Lutetium called the Lutetium octreotide therapy or PRRT (peptide receptor radiotherapy). When injected into the body, the octreotide homes in on the tumor cells, where the radiation given off by the Lutetium could kill the tumor cells. So far, results have been promising, but this treatment is not easily available at all centres.