Understanding NETs

Why are NETs so challenging for physicians and patients?

Simron Singh, MD:

Neuroendocrine tumors are all very different. Some are very aggressive. Some are very slow growing. Some are benign and some are malignant. Some are symptomatic and some are not. It's important for each patient to understand that their disease is going to be different than the next patient's. They should ask questions of their physician and get involved in a treatment plan that best suits them.

Unfortunately, for the average patient, it's quite a journey from the point when they first start having symptoms or difficulties to the point when they are actually diagnosed. NETs aren't well understood or commonly known by the medical community, and that causes a lot of problems in terms of diagnosis. Often, by the time a patient reaches me, they've seen multiple doctors and have spent sometimes years trying to explore different opinions to try to come to a conclusion about why they're having the symptoms they are having.

Eugene Anthony Woltering, MD, FACS:

NETs, by and large, are cancers in slow motion. You can have a patient who has widespread disease in their liver and lives a decade or more. The issue is the difference between survival and quality of life. In NET patients, you want to increase survival, but you want to make sure that they have a good quality of life at the same time.

Simron Singh, MD:

It's important to understand the common symptoms that are associated with NETs: flushing, diarrhea, wheezing, and abdominal pain. This constellation of symptoms should lead us toward thinking about a NET, or at least investigating toward it.

Generally, I find that, after the diagnosis, we can get these symptoms under control. We can take effective steps toward treatment to help the patients feel a lot better.

Understanding NETs

What are NETs?

Larry Kvols, MD:

Well, neuroendocrine tumors are a group of tumors that arise from cells in the body that have both neurologic and endocrine function hence the name, neuroendocrine.

Eugene Anthony Woltering, MD, FACS:

As you eat, as you breathe those endocrine cells have specific functions. Let's say, in the gut, to promote motility, to promote the correct water balance so that you're not constipated or have diarrhea. And ultimately, in rare individuals, those cells go haywire and a normal endocrine cell of the gut or a normal endocrine cell of the liver or a normal endocrine cell of the pancreas goes wacko and becomes a malignancy.

Larry Kvols, MD:

And these are cells that are ubiquitously distributed. We have them in our pituitary hypothalamus area, in our thyroid, in our lungs in the airways, in the stomach, the pancreas, the small and large intestine, and in the rectal area. So, they are truly distributed throughout the body. There are even some in the skin. So, there are neuroendocrine cancers that can arise from any of these organs.

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Understanding NETs

What are functioning and nonfunctioning NETs?

Simron Singh, MD:

A neuroendocrine tumor derives from neural cells anywhere throughout the body. Neuroendocrine tumors may or may not produce hormones. Neural cells normally are able to secrete specific peptides and hormones. In a functioning NET, the neuroendocrine cells have lost the ability to regulate that activity and they oversecrete peptides or hormones, which can cause symptoms in patients.

Eugene Anthony Woltering, MD, FACS:

Some patients are referred to me because they have a NET of the pancreas and their tumor is functional or hormonally active. Functional tumors can produce insulin, which would cause hypoglycemia; they can produce something called VIP, or vasoactive intestinal peptide, which causes diarrhea; they can secrete glucagon, which causes skin rashes and diabetes; they can secrete somatostatin, which causes mild diabetes and stones in the gallbladder; or they can make what's called gastrin, which causes unremitting ulcer disease in the stomach, duodenum, and upper small bowel.

On the other hand, some patients who have tumors in the pancreas present with no functional abnormality. They purely present with pain and obstruction of the pancreatic duct. Or, they might have an obstruction of the common bile duct which causes them to turn pumpkin colored. Some of these patients are ultimately found on biopsy not to have a pancreas cancer of the common variety, but a NET.

Understanding NETs

What are the symptoms NETs cause?

Simron Singh, MD:

There's a wide variety of symptoms that someone with a neuroendocrine tumor can experience. They can range from very generalized symptoms like abdominal pain, nausea, even vomiting to feeling unwell to much more specific symptoms like flushing (multiple times a day often), diarrhea, wheezing, or what we call bronchial spasm.

Frederico Costa, MD:

The general symptoms that those patients with neuroendocrine tumors can present varies, depending on the type of the tumor we are talking about. It could cause symptoms like flushing (the skin turns red). You also can have some bronchial spasms. You can have severe diarrhea. You can have, chronically, some heart problems associated to that, and this combination of symptoms are called carcinoid syndrome. So, it's interesting because the symptomatology of those tumors, it's not something that I measure in the blood. It's how the patient feels it.

Simron Singh, MD:

If I was a patient and I presented with flushing, diarrhea, wheezing or generalized abdominal pain, I would definitely ask my physician if they had thought about neuroendocrine cancer as part of a possible diagnosis.

Philippe Ruszniewski, MD:

In carcinoid tumors, sometimes and rather frequently, diarrhea is associated with flushing, which is this reddish color of the face and the upper part of the body which might happen in different situations (such as anxiety, alcohol intake, and so on). And in this situation, of course, when you have both flushing and diarrhea, it's highly likely that you have a carcinoid syndrome, and then a carcinoid tumor.

Eugene Anthony Woltering, MD, FACS:

The doctors who refer patients to me suspect NETs, again based on location. A few of them that I see are referred to me because they had pneumonia, or they coughed up blood and they were found to have a NETs-type of tumor of the bronchial tree (the breathing tubes in the chest). Some patients are referred to me because they have a NET of the pancreas and their tumor is functional or hormonally active and those tumors can produce insulin, which would present with hypoglycemia. Some of those patients who have tumors in the pancreas present with no functional abnormality. They purely present with pain and obstruction of the pancreatic duct, or they obstruct the common bile duct and people turn pumpkin-colored. They're found ultimately on biopsy not to have a pancreas cancer of the common variety, but a neuroendocrine tumor. And then there are the physicians who are faced with patients who have unremitting diarrhea that are often misdiagnosed for years as having irritable bowel syndrome.

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Understanding NETs

What can I do to better understand my condition?

Myra Piracci:

I think the best way (or one of the best ways) to fight cancer is knowledge. You have to learn as much as you can. One of the most frightening things for everyone that I speak to is making those decisions. A few of my doctors recommended a support group, and I really resisted that. I felt I had a lot of support in my family and my friends, and I really didn't want to go to a support group. When I did, it was an enormous amount of power from knowledge from all the information I learned from the other people. It was probably the single best thing that I did.

Maryann Wahmann:

When I first was diagnosed, of course, your first fear is: "Is this cancer? Am I going to die?" I reached out to the Carcinoid Cancer Foundation, started reading a lot of information, and started going to speak to online groups to find out that there are patients that live 20 years, if it's caught early enough and that you can live with this. It's not curable, but it can be controlled.

Thomas Defrancisci:

Taking charge of my own information and healthcare has been the single biggest thing that I've learned at the support groups the single biggest thing I've learned online. Because carcinoid is so rare, there's a lot of misinformation about it, particularly in the medical profession. I met many doctors (not many, but some doctors) that don't even consider it to be a malignancy a cancer. My own doctors were very up-to-date on carcinoid. I was fortunate in that way.

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Diagnosing NETs

Why does it take so long to diagnose a NET?

Eugene Anthony Woltering, MD, FACS:

People who have neuroendocrine tumors of the lung most commonly present with pneumonia, bleeding called hemoptysis, or fever and chills. Those people with tumors in the gut often present with diarrhea, wheezing, or with flushing.

Physicians also might be faced with patients who have unremitting diarrhea who are often misdiagnosed for years as having irritable bowel syndrome. They have alternating constipation and diarrhea early on, and then later they have diarrhea every day that goes from 1 or 2 stools in the morning to 2 or 3 stools throughout the day, to 3 or 4 or 5 stools. The antimotility drugs don't work anymore. And that's when the physician needs to consider the more esoteric or "zebra-like" diagnosis. In medical school we're taught that if you hear a hoofbeat, there's always a horse around, but occasionally it's a zebra. And that's what these neuroendocrine tumors are: the zebras of the tumor world.

Simron Singh, MD:

The typical patient who's been diagnosed with a NET has been through quite a bit - probably more than the average patient. They've often visited many different physicians searching for an answer to their difficulties and have done a lot of self-education on the Internet. The first piece of advice I would give to these patients is to not panic. They might want to discuss the situation with their family doctor and maybe read up on NETs themselves. I think specific tests to ask for include chromogranin A and urinary 5-HIAA.

If the patient is not satisfied with that, I think it's important to go to a physician who has an interest or at least some level of expertise in this type of tumor.

NET patients often come in with such a fear that no one really knows about this type of tumor. It's important to allay these fears and let them know that there are treatment options. I think that's an important message to get across to patient groups.

Diagnosing NETs

Why are NETs so elusive?

Simron Singh, MD:

Unfortunately, neuroendocrine tumors aren't well understood, I think, or commonly known by the medical community. And that causes a lot of problems in terms of diagnosis. Often by the time a patient reaches me, they've seen multiple doctors−and have spent, sometimes up to years−trying to explore different opinions to try to come to a conclusion about why they're having symptoms that they are.

Frederico Costa, MD:

Sometimes the patient doesn't realize that he has a problem. Second, the physician−if he is not really thinking on the diagnosis−sometimes he can miss it because, as you know, the symptoms can overlap with a bunch of diseases.

Eugene Anthony Woltering, MD, FACS:

If you hear a hoof beat, there's always a horse around. But occasionally, if you hear a hoof beat, it's not a horse; it's a zebra. And that's what these neuroendocrine tumors are called: the zebras of the tumor world. And their diagnosis will be triggered by a specific syndrome or a specific symptom.

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Diagnosing NETs

How can I tell if my diarrhea might be caused by a NET?

Philippe Ruszniewski, MD:

The most frequent symptom of digestive neuroendocrine tumors is probably diarrhea. Diarrhea, of course, is very common. So it is very difficult for the gastroenterologist, and even more so for the general practitioner, to be able to make the diagnosis of a NET in a patient with chronic diarrhea.

The diarrhea associated with carcinoid syndrome is what we call a motor diarrhea. In motor diarrhea the patient feels an urgency in going to the bathroom, and the stool might contain nondigested food. The patient may have a lot of small stools following meals, and they might also have to go to the bathroom during the night.

Frequently in carcinoid syndrome, diarrhea is associated with flushing, which is a reddish color of the face and the upper part of the body. When you have both flushing and diarrhea, it's highly likely that you have a carcinoid syndrome, which could mean you have a NET.

When diarrhea is unexplained with upper and lower GI endoscopies, with biopsies of the duodenum and the colon, then the gastroenterologist should really think about an endocrine tumor. They should do 2 things: determine hormone levels in the blood to see if there is a hormone secreting in excess; and do imaging procedures in order to look for the tumor that should be responsible for the symptoms.

Diagnosing NETs

Why is early diagnosis important?

Simron Singh, MD:

Well, I think in all cancers (but, specifically, in neuroendocrine cancers), the earlier we can find the disease the more effective options we have of controlling it, and hopefully curing it.

Larry Kvols, MD:

What does it mean to have earlier diagnosis? Well, this is critical because the earlier we can diagnose these problems, the more likely we are to be able to cure them. And surgery is usually the definitive treatment for these tumors, if we're fortunate enough to detect them early. So, an astute physician, who recognizes the symptoms that the patient is describing, may be able to work with a surgical colleague and intervene surgically before the cancer has actually spread.

Frederico Costa, MD:

Now, once it's detected, a recurrence of the disease could be curable, depending on how early the diagnosis is done. That's why it's important. A close follow-up of this disease with a center that has some expertise on the treatment of neuroendocrine tumors.

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Diagnosing NETs

If I think I have a NET, what should I tell my doctor?

Maryann Wahmann:

My advice to any patient, who has been treated by a doctor who says that they can't find anything wrong, is to keep looking because you know your own body. Don't always take the doctor's answer for granted and just keep searching. Search the Internet. Search for doctors to get the right answer. Had I not continued the search, I don't know if I would still be here today.

Simron Singh, MD:

If I was a patient and I presented with flushing, diarrhea, wheezing or generalized abdominal pain, I would definitely ask my physician if they had thought about neuroendocrine cancer as part of a possible diagnosis.

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Diagnosing NETs

What tests are used to diagnose NETs?

Eugene Anthony Woltering, MD, FACS, MD:

If you have biochemical abnormalities that indicate that you have a NET, the next thing would be to do the radiologic and nuclear medicine evaluation. That would be a CAT scan of the abdomen and OctreoScan (the total body). And then if you have a suspicion of a lesion in the liver, an MRI using gadolinium enhancement.

Frederico Costa, MD:

So, biopsy is very important – not only to get a good sample, but sometimes to have a good pathologist in your hand. Sometimes the pathologist that made the initial diagnosis is not an expert in this field, so it's commonly necessary to have a second opinion on the pathology. It may take a little time, but it's very important to have it.

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Diagnosing NETs

What is the role of CgA in helping diagnose my NET?

Eric Baudin:

As soon as we know that we are facing a neuroendocrine tumor, then we measure CgA. If you have an increased tumor burden, you increase the chance to have high levels of chromogranin A measurements. So, first answer: yes, chromogranin A is related to tumor burden and that's why it is considered as an interesting tumor marker in neuroendocrine tumors.

Larry Kvols, MD:

Chromogranin A is a molecular marker that can be determined from a simple blood draw; it doesn't require a biopsy. And it's one of the most useful markers for detecting neuroendocrine tumor tissue. When a chromogranin A comes back elevated, it is not proof positive that you have a neuroendocrine tumor. It's important that one keep in mind that there are situations that can give rise to so−called false positives. So, if these things are kept in mind−impaired renal function, proton pump inhibitors, chronic inflammatory conditions and inflammatory states−then a positive or elevated chromogranin A should make one very suspicious that you might be dealing with an underlying neuroendocrine tumor, and pursue further testing.

Joy Ardill:

There will be 10% or 15% that will give a negative chromogranin A. Insulinoma is the most common neuroendocrine tumor of the pancreas and they tend, sometimes, not to have a raised chromogranin A. But, then, insulin or parts of insulin (pro-insulin or C-peptide) are very good markers.

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Managing NETs

What are some of the treatments for NETs?

Larry Kvols, MD:

We're always going to be thinking about surgery as the number one approach to treatment because, if we can resect the disease, then the patient is going to have a much better quality of life and a more prolonged survival.

Simron Singh, MD:

The most important thing a patient with metastatic neuroendocrine tumor needs to know, I think, is that there are treatment options − that each of the tumors is unique, and the treatment decisions are different for each patient. And I would advise that they try to seek care at a center where there are some expertise, or at least interest, in neuroendocrine tumors.

So, for early stage neuroendocrine cancers, I think the best treatment is surgery and resection of the disease itself. Once the disease has spread, we still have options, and they generally involve combinations of surgery, of medical treatment, and often of different types of unique treatments such as radiofrequency ablation or chemoembolization.

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Managing NETs

Why are different experts involved in managing NETs?

Myra Piracci:

You really need the team of doctors. The experts will always tell you that. And it's so true because the doctors that you think the most of, no one is going to have all those answers. You need the surgeon and the medical oncologist. You need the combination of doctors to really help you make the best decisions.

Simron Singh, MD:

I think, from a patient's point of view, it's important that they seek attention in a center that has some experience or some interest in neuroendocrine tumors. Often, these centers treat these tumors in a multidisciplinary fashion and develop treatment plans that involve different type of ways of treating the cancer which, I think, has been shown to lead to better outcomes.

Larry Kvols, MD:

Because there are so many therapeutic options available for the patient with neuroendocrine tumors, it's important that they are seen at a clinic specializing in these tumors that has a multidisciplinary approach − including medical oncologists, endocrinologists, the gastroenterologists, the surgeon, nuclear medicine physicians and radiologists. Only by bringing all of these specialties to bear on an individual patient's problem can we optimize care for these patients, because there are so many different options and each specialist brings a different perspective. So, it's important to integrate that care, and use it in a timely fashion.

Eugene Anthony Woltering, MD, FACS:

A multidisciplinary approach to these patients is really critical because no matter how smart I am−and I've been doing this for 30, 35 years; I have a lot of experience−I don't have the depth of knowledge of chemotherapy as my partner who's a medical oncologist.

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Managing NETs

How can a NET affect my life?

Maryann Wahmann:

It was very tough on me and my husband and my family: Hearing the word "cancer," #1; #2, having the diarrhea was very immobilizing I couldn't leave the house because I had to stay close to the bathroom. There were times when I was so tired from going to the bathroom all the time, I spent a lot of time in bed. However, once I got onto the surgery and I got onto the proper treatment, I live a full life now and an active life.

Bob Pustarfi:

Well, my whole life changed around. When I say changed around, I was at the age of 65. I would say in my prime, and I'm not a couch potato. I still do what I do; it's not going to stop me. Nothing's going to stop me. Your moods you get a mood swing you don't realize it. People say, "Gee, you know you're grumpy? What happened?" And you say, "I'm not grumpy. I'm still the same." But then you start saying, "You know what? I am changing." It tries to run you, but you've got to remember: "Don't let it run you. You run it."

Myra Piracci:

As much as people say, "Oh, it's amazing, how do you do that?" You don't really have a choice, you know. I would rather have a good attitude about it. I don't want to walk around gloomy that's not any fun. So, I try to avoid that as much as I can, but it's definitely made life interesting.

And, as crazy as it sounds when you hear people say this, I've met fabulous people through this. But, it's so true. You meet people that have just been through so much and, no matter how bad your story is, there's always somebody that's been through more.

Thomas Defrancisci:

Well, I consider myself very fortunate because a part of what the doctors say did come true: after the surgery, the healing process from the lung surgery was very rapid-remarkably rapid−to the point where I was able to run again. I ran in a 10K race less than three months after surgery. So, for me, it was not too hard once I accepted that I needed surgery.

Grace Mulligan:

Managing my day-to-day life and emotional well-being, I don't know. I'm still here, so that's enough maybe. But, my husband is my caretaker. He is the one who obsesses. And every doctor's appointment, he's got a bag full of the latest blood work, any kind of scans, and he updates every doctor. He's the one who measures out my pills. He does my worrying for me. For anyone who has cancer and a caretaker, tell them you love them every day and every time you can show appreciation for them. Do it because they are your lifeline more than anything.

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