Diabetes – The NET Effect


My chest infection is now settled, as too is the excitement and apprehension behind my first ever Ga68 PET – the outcome of that is still a work in progress. Earlier this year, my thyroid ‘lesion’ on watch and wait was given a ‘damping down’ with the prescription of a thyroid hormone supplement but I await a re-ignition of that small bush fire downstream.

Bubbling behind the scenes and clamoring for attention is the spiking of my blood glucose test results and I was very recently declared ‘at risk’ for diabetes One of my followers entitled a post in my group with “The hits keep coming” in reference to encountering yet another problem in the journey with Neuroendocrine Cancer. I now know how she feels, this issue is a bit of a ‘left fielder’. However, having analysed the situation and spoken to several doctors, I can now put pen to paper.

Neuroendocrine Cancer is not a household name (…… I’m working on that) but diabetes certainly is. The World Health Organisation reports that the number of adults living with diabetes has almost quadrupled since 1980 to 422 million adults. In USA, estimates from CDC stated around 10 million people diagnosed with diabetes with a further 84 million in pre-diabetes state (at risk). In UK around 3.7 million people have diabetes with about 4 times that amount ‘at risk’. It’s a growth industry (…….. but so is NETs – in the last 40 years, the incidence of NETs is rising at a faster rate than diabetes, a disease which some writers have described as an epidemic).

With those numbers, it follows that many NET patients will be diabetic before diagnosis, some will succumb to diabetes whether they have NETs or not, and some may have an increased risk of succumbing due to their treatment. Some may even be pushed into diabetes as a direct result of their NET type or treatment. It’s important to understand diabetes in order to understand why certain types of NET and certain treatments could have an involvement.

The Pancreas

For understanding of this article, it’s worth noting the pancreas has two main functions: an exocrine function that helps in digestion and an endocrine function that regulates blood sugar. I have talked about the exocrine function in relationship to Neuroendocrine Cancer at length – check out this article on Pancreatic Enzyme Replacement Therapy. In this article, I now want to cover the issues with the endocrine function and blood sugar. First a short primer on diabetes – it is necessarily brief for the purposes of this article.

 

Diabetes Primer

TypeS OF DIABETES

Type 1 and Type 2 Diabetes are fairly well-known. There’s actually more than two types, but these are the most common. Type 2 is the most prevalent with around 90% of diabetes cases. When you’ve got Type 1 diabetes, you can’t make any insulin at all. If you’ve got Type 2 diabetes, the insulin you make either can’t work effectively, or you can’t produce enough of it. Additional types may come up in the subsequent discussion.

What is the problem?

What all types of diabetes have in common is that they cause people to have too much glucose (sugar) in their blood. But we all need some glucose. It’s what gives us our energy. We get glucose when our bodies break down the carbohydrates that we eat or drink. And that glucose is released into our blood. We also need a hormone called insulin. It’s made by our pancreas, and it’s insulin that allows the glucose in our blood to enter our cells and fuel our bodies.

If you don’t have diabetes, your pancreas senses when glucose has entered your bloodstream and releases the right amount of insulin, so the glucose can get into your cells. But if you have diabetes, this system doesn’t work properly. Diabetes is associated by being overweight but there isn’t a 100% correlation with that. However, when an individual becomes overweight, there is an increase in free fatty acids in the blood stream which may contribute to reduced insulin sensitivity in the tissues, leading to increased glucose levels in blood.

Symptoms and diagnosis of Diabetes

Different people develop different symptoms. In diabetes, because glucose can’t get into your cells, it begins to build up in your blood. And too much glucose in your blood causes a lot of different problems. To begin with it leads to diabetes symptoms, like having to wee a lot (particularly at night), being incredibly thirsty, and feeling very tired. You may also lose weight, get infections like thrush or suffer from blurred vision and slow healing wounds.

I see these symptoms mentioned very frequently and normally people are trying to associate them with NETs and/or the treatment for NETs.

Diabetes diagnosis is normally triggered diagnosed based on blood tests such as fasting Blood Glucose (snapshot) and/or Glycated Hemoglobin (A1C) or HbA1C.

Complications

Over a long period of time, high glucose levels in your blood can seriously damage your heart, your eyes, your feet and your kidneys. These are known as the complications of diabetes.

But with the right treatment and care, people can live a healthy life. And there’s much less risk that someone will experience these complications.

What are the direct connections with Diabetes and NETs?

It’s not surprising that diabetes is mostly associated with Neuroendocrine Tumors of the Pancreas but there are other areas of risk for other types of NETs including to those who are existing diabetics – see below.

Surgery

The main types of surgery for Neuroendocrine Tumors of the Pancreas are Distal Pancreatectomy (tail), Sub-total pancreatectomy (central/tail), Classic Whipple (pancreaticoduodenectomy – head and/or neck of pancreas), Total pancreatectomy (remove the entire pancreas) or an Enucleation (scooping out the tumour with having to remove too much surrounding tissue). From the PERT article link above (exocrine function), you can see why some people need this treatment to offset issues of reduced production of pancreatic enzymes. The same issue can develop with a reduced endocrine function leading to the development of diabetes.

NET Syndromes

The different types of functional pancreatic NETs often called syndromes in their own right due to their secretory role. One might think that Insulinomas are connected to diabetes issues but this hormonal syndrome is actually associated with low blood sugar (hypoglycemia), although low blood sugar can turn out to be a complication of diabetes treatment.

A NET syndrome known as Glucagonoma (a type of functional pancreatic NET) is associated with high blood glucose levels. About 5-10% of pancreatic neuroendocrine tumors are Glucagonomas, tumors that produce an inappropriate abundance of the hormone glucagon. Glucagon balances the effects of insulin by regulating the amount of sugar in your blood. If you have too much glucagon, your cells don’t store sugar and instead sugar stays in your bloodstream. Glucagonoma therefore leads to diabetes-like symptoms (amongst other symptoms). In fact Glucagonoma is sometimes called the 4D syndrome – consists of diabetes, dermatitis, deep venous thrombosis (DVT), and depression.

Another functional pancreatic NET known as Somatostatinoma is prone to developing insulin resistance. Somatostatinomas produce excessive amounts of somatostatin which interferes with the insulin/glucagon function and could therefore lead to diabetes.

Diabetes caused by cancer or cancer treatment

Worth noting that this type of diabetes is sometimes known as ‘Pancreatogenic diabetes’ and this is actually classified by the American Diabetes Association and by the World Health Organization as type 3c diabetes mellitus (T3cDM) and refers to diabetes due to impairment in pancreatic endocrine function due to acute cancer and cancer treatment (and several other conditions). The texts tend to point to cancers (and other conditions) of the pancreas rather than system wide. Prevalence data on T3cDM are scarce because of insufficient research in this area and challenges with accurate diabetes classification in clinical practice. (Authors note: Slightly confusing as many text say that type 3 diabetes is proposed for insulin resistance in the brain (diabetes associated with Alzheimer’s disease).  There’s another term for a complete removal of the entire pancreas – Pancreoprivic Diabetes

Other treatment risks

Somatostatin Analogues (e.g. Octreotide and Lanreotide) are common drugs used to control NET Syndromes and are also said to have an anti-tumor effect. They are known to inhibit several hormones including glucagon and insulin and consequently may interfere with blood glucose levels. The leaflets for both drugs clearly state this side effect with a warning that diabetics who have been prescribed the drug, should inform their doctors so that dosages can be adjusted if necessary. The side effects lists also indicates high and low blood glucose symptoms indicating it can cause both low and high blood glucose (hypoglycemia and hyperglycemia). For those who are pre-diabetic or close to pre-diabetic status, there is a possibility that the drug may push blood tests into diabetic ranges.
Afinitor (Everolimus). The patient information for Afinitor (Everolimus) clearly states Increased blood sugar and fat (cholesterol and triglycerides) levels in blood: Your health care provider should do blood tests to check your fasting blood sugar, cholesterol and triglyceride levels in the blood before you start treatment with AFINITOR and during treatment with AFINITOR”
Sutent (Sunitinib). The patient information for Sutent (Sinitinib) clearly states that low blood sugar (hypoglycemia) is a potential side effect. It also advises that low blood sugar with SUTENT may be worse in patients who have diabetes and take anti-diabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with SUTENT and may need to adjust the dose of your anti-diabetic medicines.

In rare cases, certain NETs may produce too much Adrenocorticotropic hormone (ACTH), a substance that causes the adrenal glands to make too much cortisol and other hormones. This is often associated with Cushing’s syndrome. Cortisol increases our blood pressure and blood glucose levels with can lead to diabetes as a result of untreated Cushing’s syndrome.

Summary

I think it’s sensible for all NET patients, particularly those with involvement as per above and who are showing the signs of hypoglycemia and hyperglycemia, to be checked regularly for blood glucose and if necessary HbA1c. Many patient information leaflets for the common NET treatments also indicate this is necessary. Always tell your prescribing doctors if you are a diabetic or about any history of low or high blood glucose before treatment for NETs.

My brush with Diabetes (as at Jan 2019)

My blood glucose levels started to climb slightly in 2016 but HbA1c remained normal. However, an HbA1c test in early 2018 put me into pre-diabetic range (44 mmoL/moL). I explained some of the above article to my GP who is corresponding with a diabetes expert at secondary care – the expert suggested that I need to be monitored carefully as weight loss is not necessarily the best response. I have kept my NET team up to date.

At the time of updating, two separate and sequential HbA1c tests (3 month interval) came back normal at 36 mmoL/moL.  I’m pragmatic enough to know that I do not need to lose weight as one of the aims of reducing my blood glucose and HbA1c levels (something emphasised by the above mentioned diabetes specialist).

I even got on my bike to do a little bit more exercise just in case!

At this point, I cannot yet say if this is the beginning of progressive Type II diabetes or if my medication is causing these spikes in my blood glucose and HbA1c. Judging by 2 x normal HbA1c, looks like the somatostatin analogue (Lanreotide in my case) may caused a spike to a pre-diabetes score.  I will keep you posted.

Summary – if you are noticing these symptoms, get your blood sugar checked (with acknowledgement to Dr Pantalone from Cleveland Clinic)

1. You’re making more trips to the bathroom

Having to go to the bathroom more than normal, particularly at night, is a sign that your blood sugar might be out of whack.

Dr. Pantalone says one of his patients came in for a diagnosis after a family member noticed that he was using the bathroom during each commercial break when they watched TV.

2. You’re getting frequent urinary or yeast infections

When your blood sugar is high and your kidneys can’t filter it well enough, sugar ends up in the urine. More sugar in a warm, moist environment can cause urinary tract and yeast infections, especially in women.

3. You’re losing weight without trying

If you have diabetes, your body isn’t able to use glucose (sugar) as effectively for its energy. Instead, your body will start burning fat stores, and you may experience unexpected weight loss.

4. Your vision is getting worse

High sugar levels can distort the lenses in your eyes, worsening your vision. Changes in your eyeglass prescription or vision are sometimes a sign of diabetes.

5. You’re feeling fatigued or exhausted

Several underlying causes of fatigue may relate to diabetes/high sugar levels, including dehydration (from frequent urination, which can disrupt sleep) and kidney damage.

This feeling of exhaustion is often persistent and can interfere with your daily activities, says Dr Pantalone.

6. You’re noticing skin discoloration

Something that Dr. Pantalone often sees in patients before a diabetes diagnosis is dark skin in the neck folds and over the knuckles. Insulin resistance can cause this condition, known as acanthosis nigricans.

 

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

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NET Syndromes – chicken or egg?


We’ve all heard the age-old question about the chicken and the egg?  Scientists claimed to have ‘cracked’ the riddle of whether the chicken or the egg came first. The answer, they say, is the chicken. Researchers found that the formation of egg shells relies on a protein found only in a chicken’s ovaries. Therefore, an egg can exist only if it has been inside a chicken. There you have it!

On a similar subject, I’m often confused when someone says they have been diagnosed with ‘Carcinoid Syndrome’ and not one of associated ‘Neuroendocrine Tumours’.  So which comes first?  I guess it’s the way you look at it. In terms of presentation, the syndrome might look like it comes first, particularly in cases of metastatic/advanced disease or other complex scenarios.  Alternatively, a tumour may be found in an asymptomatic patient, quite often incidentally.  However, on the basis that the widely accepted definition of Neuroendocrine Tumours would indicate that a syndrome is secondary to tumour growth, then the tumour must be the chicken.

I sometimes wonder what patients are told by their physicians….. or perhaps by their insurance companies (more on the latter below). That said, I did see some anecdotal evidence about one person who was diagnosed with Carcinoid Syndrome despite the lack of any evidence of tumours or their markers. This might just be a case of providing a clinical diagnosis in order to justify somatostatin analogue treatment but it does seem unusual given that scientifically speaking, Carcinoid Syndrome can only be caused by a particular type of NET.

I have a little bit of experience with this confusion and it still annoys me today.  Shortly after my diagnosis, I had to fill out an online form for my health insurance.  The drop down menu did not have an entry for Neuroendocrine ‘anything’ but I spotted Carcinoid only to find it was actually Carcinoid Syndrome.  By this stage I had passed the first level of NET knowledge and was therefore suspicious of the insurance company list.  I called them and they said it was a recognised condition and I should not worry.  Whilst that statement might be correct, I did tell them it was not a cancer per se but an accompanying syndrome caused by the cancer. I added that I was concerned about my eligibility for cancer cover treatment and didn’t want to put an incorrect statement on the online form. However, they persisted and assured me it would be fine on that selection.  On the basis it was really the only option I could select, I selected and submitted.  I did get my cover sorted.  However, it’s now clear to me that their database was totally out of date.  A similar thing happened when I was prescribed Octreotide and then Lanreotide, the only ‘treatment type’ they could find on their database was ‘chemotherapy‘ – again their system was out of date.  I’m told by someone in the know, that individual insurance companies are not responsible for this list, they all get it from a central place  – I’d love to pay that central place a visit!

I quickly thought about all the other NET Syndromes for their ‘chicken and egg’ status! Pancreatic NET (pNET) Syndromes must all be ‘chicken’ given the tumour definition and the secretion of the offending hormones that cause these other syndromes e.g. Insulin, Gastrin, Glucagon, Pancreatic Polypeptide (PP), Vasoactive Intestinal Peptide (VIP) and Somatostatin, etc.

All of that said, the exception might be hereditary syndromes e.g. MEN (yes it is a syndrome, not a tumor type).  MEN syndromes are genetic conditions. This means that the cancer risk and other features of MEN can be passed from generation to generation in a family. A mutation (alteration) in the various MEN genes gives a person an increased risk of developing endocrine/neuroendocrine tumors and other symptoms of MEN. It’s also possible that the tumors will be discovered first.  It’s complex as you will see in my article entitled “Genetics and Neuroendocrine Tumors”.

 

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

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Steve Jobs – the most famous Neuroendocrine Cancer Ambassador we NEVER had

steve jobs 2010
The last few years have reminded me that life is fragile

Steve Jobs died 5 Oct 2011.  RIP Steve, you certainly made a difference to the world of technology and that is still being felt today.  I have a number of google alerts setup and every day the emails arrive in my inbox. The longest email is always the Steve Jobs one, i.e. Steve Jobs is written about more than Neuroendocrine Cancer and other connected subjects. That’s interesting because Neuroendocrine Cancer is the type Steve had, not Pancreatic as is frequently reported.

There are huge differences between Pancreatic Cancer and Neuroendocrine Cancer with a pancreatic primary – click here to read more. 

pancreatic vs neuroendocrine

I’ve mentioned Steve Jobs a few times previously, mainly in my blog The Human Anatomy of Neuroendocrine Cancer. I wrote that blog when I was frustrated about the constant misreporting of Neuroendocrine Cancer as other types of cancer. Others included Nick Robinson (see blog The Devil is in the Detail) and Wilko Johnson (The Ecstasy of Wilko Johnson).  I’ve also suggested in my blog ‘Every Day is NET Cancer Day’ that we need high-profile patient Ambassadors and despite his death, Steve Jobs would have been quite a catch, had he been willing. Curiously, the same thing is happening with Dag Kittlaus (Siri creator) who was diagnosed with a pNET last year.  To add insult to injury, the 2018 death of Aretha Franklin is gong the same way.

A lot has been written about Steve’s cancer experience and much of it is full of ‘what ifs’. However, I’d like to focus on the facts that are known and we can be almost certain about. That said, the precise detail that we (as NET patients) might want, is probably only to be found in Steve Jobs’s medical documents. Many people say that Steve Jobs had a right to personal privacy and I agree, nothing I put here isn’t already in the public domain.

Diagnosis

How was it found?  In 2003, Steve was having a CT scan to examine his kidneys and ureter, as he had developed recurrent kidney stones beginning in the late 1990s. A suspicious lesion was spotted on his pancreas. To cut a long story short, he eventually had more specialist scans and then a biopsy which diagnosed a type of Neuroendocrine Tumour.  There are many mentions of Insulinoma, a pNET which is reported to have a 10% malignancy rate (ISI Book – Woltering et al). It isn’t clear whether Steve had any presentational symptoms of an Insulinoma at this point (i.e. hypoglycemia).  There is also some chatter online about his tumour being a Glucagonoma (another type of pNET).

Initial Treatment

Steve initially tried alternative medicine before having surgery 9 months after diagnosis. There are reports of his medical team urging surgery earlier and his biographer stated that Steve had later regretted this delay. One of his Doctors is reported to have said “Steve was a very thoughtful person. In deciding whether or not to have major surgery, and when, he spent a few months consulting with a number of physicians and scientists worldwide as well as his team of superb physicians. It was his decision to do this”.  He is reported to have gone on to have a ‘Whipple’ type operation in 2004.  It was only then, that his condition was made public.  During that operation, 3 lesions were reported on his liver.

Ongoing Treatment and Surveillance

Most NET patients enter this phase after their initial treatment, it’s also the period where you learn about the cancer and how best to live with it.  There’s not much written about Jobs’ illness between his surgery and his liver transplant but my research uncovered a useful timeline from Bloomberg and other sources:

June 12, 2005: Jobs talks about his fight with cancer during a commencement speech at Stanford University. He says he was diagnosed about a year earlier and that doctors told him he wouldn’t live longer than six months. The cancer turned out to be a form that was treatable with surgery, “and I’m fine now,” he says. Source Bloomberg.  {Author’s note:  an indication he had been told, or his doctors knew, it was a Neuroendocrine Tumor}

January 24, 2006:  Walt Disney chief executive Bob Iger knew early on that Steve Jobs’s cancer had returned and kept it a secret before it became public knowledge, a new biography of Apple’s late chief executive reveals. The day the deal was officially announced, Mr Iger said he was at Pixar’s headquarters for the ceremony when Jobs asked to go for a private walk. On a secluded part of the Californian campus Jobs put his arm around Mr Iger’s shoulder and revealed his cancer was back. “Frankly, they tell me I’ve got a 50-50 chance of living five years,” the Disney CEO quoted Jobs as saying.

2007:  Not much out there except that he was busy launching what might be regarded as Apple’s most successful and iconic product ever – the iPhone.

June 9, 2008: Jobs, while introducing the iPhone 3G at Apple’s developers’ conference, appears thinner and frail. The company blames a “common bug.”

July 21, 2008: Responding to concerns about Jobs’s appearance, Apple says he has no plans to leave the company and that his health is a private matter. Investors aren’t reassured, and the shares fall 10 percent.

July 23, 2008: The New York Times reports that Jobs has been telling associates and Apple’s board he is cancer-free. Jobs had a surgical procedure earlier in the year to address a problem that contributed to his weight loss, the newspaper reports, citing unnamed people close to the executive. The shares climb 2.6 percent.

July 26, 2008: New York Times columnist Joe Nocera writes that he spoke two days earlier on the phone with Jobs, who said his health problems weren’t life-threatening. Jobs declines to go on the record about the nature of his ailment.

Sept. 9, 2008: Jobs, introducing new iPod media players at an event in San Francisco, still looks thin. “Reports of my death are greatly exaggerated,” Jobs jokes. Munster says that while the CEO’s appearance is unchanged since June, “Just the fact that Steve Jobs was up there was a positive.”

Oct. 3, 2008: A posting on CNN’s citizen journalist Web site, called iReport.com, says Jobs has been rushed to the hospital after a “major heart attack.” The shares fall 5.4pc. The stock rebounds after Apple says the report is false.

Dec. 16, 2008: Apple says that Jobs won’t be giving his usual speech at the Macworld conference, renewing concerns about his health. Jobs had used the forum to introduce new products for 11 straight years.

Jan. 5, 2009: Jobs says he is suffering from a hormone imbalance, causing him to lose weight. Jobs vows to remain CEO during treatment. “The remedy for this nutritional problem is relatively simple and straightforward,” Jobs says in an open letter.

Jan. 14, 2009: Jobs gives up day-to-day operations to Cook until June, saying his health problems are more complex than originally thought. Jobs says he will remain involved in major strategic decisions. “I look forward to seeing all of you this summer,” he says in a letter to employees.

By this stage, his cancer is already starting to take its toll on how he looks.

The disease takes its toll over the years

Liver Transplant 2009

It is common knowledge that Jobs had a liver transplant in 2009 in Tennessee (he was on the list in California and Tennessee).  In between his Whipple and then, he appears to have lived (and worked) with his disease and it’s consequences. His issues appear to have been exacerbated by his excessive vegan diet/fads and the effects of the Whipple surgery (many of you will be aware of these effects). For example, he would spend weeks eating the same thing and then suddenly change his mind and stop eating it. He’d also go on fasts. His condition immediately prior to the liver transplant was said to be ‘poor’ and losing more weight (he had been noticeably thinner for some time).

Did Steve Jobs get ‘experimental’ PRRT?

Jobs took a second medical absence for roughly six months in 2009. It wasn’t until June 20th, two months after the fact, that the Wall Street Journal uncovered the fact that Jobs had undergone a secret liver transplant at Methodist University Hospital in Memphis, Tennessee. However, during that absence, Fortune reported Jobs also took an unpublicized flight to Switzerland to undergo an ‘unusual radiological treatment’ (PRRT) at the University of Basel for neuroendocrine cancer, according to Jerry York, the Apple director who died in March 2010.

Post-Liver Transplant

In 2010, Jobs started to feel sick again. He would lose his appetite and begin to feel pains throughout his body. His doctors would do tests, detect nothing, and reassure him that he still seemed clear.  In early November 2010, he was in pain, stopped eating and had to be fed intravenously by a nurse who came to his house. The doctors found no sign of more tumours, and they assumed that this was just another of his periodic cycles of fighting infections and digestive maladies.

Heres’ a great bunch of TV interviews (something Jobs didn’t do very often).  “The last few years have reminded me that life is fragile”.  Click here (worth watching the whole 10 minutes). His final TV appearance was in June 2011 to the Cupertino City Council about the acquisition of land for their new campus.  Worth watching some of it: Click here.

The End

In early 2011, doctors detected the recurrence that was causing these symptoms. Ultimately, he developed liver, bone, and other metastases.  He had a further extended leave of absence from his job before stepping down as Apple CEO in Aug,  Steve Jobs eventually died 5 Oct 2011.

steve jobs 2010
The last few years have reminded me that life is fragile

References

Notwithstanding the Pancreatic Cancer vs Neuroendocrine Cancer issue, I carried out my research mainly using two articles of the many you can find out there:

  1.  “And one more thing” about Steve Jobs’ battle with cancer
    This is a long article and totally fascinating.  Some of the evidence is presented using extracts from Walter Isaacson’s book ‘Steve Jobs’
  2. A Tumor Is No Clearer in Hindsight.  This article comes to similar conclusions than the one above but it’s shorter and easier to read. It’s from the New York times and was written after the dust settled on Jobs’ death (i.e. when more facts were available). There is also input to this article from NET specialists Dr Wolin and Dr Libutti.

  3. Apple chief Steve Jobs: Health timeline since 2003.  This article is from a UK National Newspaper (The Telegraph) but via US Business Publication Bloomberg.

Personal Summary

“A tumor is no clearer in hindsight” is a good summary on the basis that I would have liked much more detail!  During my research, I found many mentions of Insulin as stated above but only one or two mentioning Glucagon, a hormone associated with another pNET type – Glucagonoma. However, looking at this tumor type in the ISI Book (Woltering et al) and the Jobs diagnostic and treatment story, I have some doubts whether this was the precise tumor type. I have some other searches in progress hoping to find something concrete.

Thinking Differently There is no doubt that Steve Jobs was an amazing and very interesting character.  You just can’t see Apple being the Apple it is today without his intervention.  He was famous for being ‘unconventional’ and ‘thinking different’ and I get that element of his character.  I just can’t help thinking that perhaps he should have been more ‘conventional’ with this thinking and approach to treating his cancer. However, we just don’t know what advice he was receiving and what advice he accepted or rejected.  As for the ‘Pancreatic Cancer’ thing – I’ve said this before, I believe patients only say or interpret what their doctors say to them in regards cancer type.

“The most famous patient ambassador we never had”.  I don’t mean any disrespect by that, I’m just emphasising that we need so much more awareness of our cancer and a high-profile patient could do so much to help in this area. If he was so inclined, Steve would have been a fantastic advocate for Neuroendocrine Cancer and there’s an area where perhaps thinking different might be the way ahead. However, I have a suspicion that very famous people don’t really want to talk about their illness and Steve Jobs might even perceive that as a weakness.

And one more thing …….  you may also find this article useful.  It’s titled “And one more thing”

 

Neuroendocrine Cancer – tumour markers and hormone levels


blood

I think most people have had a form of medical testing at some point in their life, i.e. the sampling and testing of blood, urine, saliva, stool or body tissue. In a nutshell, the medical staff are just measuring the content of a ‘substance’ and then taking a view whether this is normal or not based on pre-determined ranges. These tests are normally done as a physician’s reaction to symptom presentation or maintenance/surveillance of an existing diagnosed condition. Sometimes, abnormal results will lead to more specialist tests.

In cancer, these tests are frequently called ‘markers’. Most tumour markers are made by normal cells as well as by cancer cells; however, they are produced at much higher levels in cancerous conditions. These substances can be found in the blood, urine, stool, tumour tissue, or other tissues or bodily fluids of some patients with cancer. Most tumour markers are proteins. However, more recently, patterns of gene expression and changes to DNA have also begun to be used as tumour markers.  Many different tumour markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with two or more cancer types. No “universal” tumour marker that can detect any type of cancer has been found.

markers

There are some limitations to the use of tumor markers. Sometimes, noncancerous conditions can cause the levels of certain tumor markers to increase. In addition, not everyone with a particular type of cancer will have a higher level of a tumour marker associated with that cancer. Moreover, tumour markers have not been identified for every type of cancer. Tumour markers are not foolproof and other tests and checks are usually needed to learn more about a possible cancer or recurrence.

I’d also like to talk about a group of associated tests, in particular, hormone levels as these tests are really important to help determine the type of Neuroendocrine Tumour.  NETs will sometimes oversecrete hormones and this can give clues to the type.  The constraints mentioned above apply to hormone levels and other tests to a certain extent.

What this article will not cover

Routine Testing – the post will not cover routine blood tests (i.e. complete blood count etc).  Although they may point to a problem, these tests do not necessarily indicate a particular type of NET without other supporting evidence.

Biopsy Testing – Technically, the Immunohistochemical ‘stains’ used in biopsy testing are tumour markers but I’ll not be discussing that today. I did cover the output of biopsies in my blog on NETs – Stages and Grades.

Genetic Testing.  This is very specialised but you may find my Genetics and NETs article is of interest.

Sequencing of marker testing – diagnosis

The sequencing of marker testing may have been different for many patients.  In my own experience, I had a biopsy and then the biochemical checks were carried out. So regardless of the results of my marker tests, I was to be diagnosed with NETs. Those with lengthy and difficult diagnostic phases will perhaps have had a different sequence with the biochemical markers providing evidence for further tests to formally diagnose.  Markers alone will normally not be enough for a diagnosis but they do, however, feed into the treatment plan and provide a baseline at diagnosis and for tracking going forward.

Interpreting test results – International/National/Regional differences

The use of markers tends to be different on an international basis, e.g. specific marker tests can be developed in-country by independent labs. Testing can also vary in the same country as in-country labs use different commercially available ‘testing kits’. Not all tests are available in all countries.

Reference ranges can be dependent on many factors, including patient age, gender, sample population, and test method, and numeric test results can have different meanings in different laboratories. The lab report containing your test results should include the relevant reference range for your test(s). Please consult your doctor or the laboratory that performed the tests to obtain the reference range if you do not have the lab report. Moreover, the ‘normal’ test range can vary from hospital to hospital, even within the same tests. I suspect clinical staff have their own versions of risk thresholds when dealing with test results. Even when results are just above or below, individual physicians can take their own view in a subjective manner. Testing is best done at the same lab each time if possible.

There’s a great website called LabTestsOnline which can describe each test. It’s peer-reviewed, non-commercial and patient-focused but just please note you should always refer to your own lab ‘normal ranges’ which will be printed on your test results.  For these reasons, you will not find reference ranges for the majority of tests described on this web site.  The link above will take you to the list of ‘country’ affiliated versions with specific information on a country basis.

Here’s some tips I always give people:

1 – Always try to get your own copy of results (preferably on paper) and track them yourself (I use a spreadsheet).

2 – When comparing results inside patient forums, always add the range and if possible, the unit of measurement (i.e. g/L, mmol/L, umol/L etc etc).  Failure to do this can at best confuse, and at worst frighten patients.  Compare apples with apples not with pears! (this is why it’s important to know the unit of measure and the reference range in addition to the figure).

3 – Don’t get too excited about rises if the test is still inside the normal range – normal is normal!

4 – Don’t get too excited about rises taking you just outside of normal range – your doctors are looking for bigger spikes.

5. Don’t get too excited about a single test result, your doctors are looking for trends, a single test result is not much to go on.

NET Markers

Although some routine blood markers (complete blood count etc) are useful in NETs, it’s pretty much impossible to cover these in any general detail.  I’m going to focus on tumor and hormone associated markers

There are many markers involved with NETs. Some do different jobs and some are just variants measuring the same thing (more or less efficiently). You may also see something called ‘gold standard’ in reference to NET Tumour markers. Although thinking is changing (more on this below) and can vary from country to country, it is generally accepted that Chromogranin A and 5HIAA are the gold standard markers for tumour bulk and tumour functionality respectively.  These gold standard tests may not be applicable to every type of NET, particularly 5HIAA. I’m also aware that US doctors are reducing the dependency on CgA and using Pancreastatin instead (although many are measuring both).

NETs are known to be heterogeneous in nature (i.e. consisting of or composed of dissimilar elements; not having a uniform quality throughout).  Whilst some markers can be used widely, it follows that there are many very specialist marker tests for individual types of NET.  I think this applies to 3 broad categories of NETs: Tumours known to potentially oversecrete Serotonin and and perhaps others (mainly midgut), Pancreatic NETs (or pNETs) secreting various hormones by type; and other less common types and/or syndromes which might be considered by some to be even more complex than the former two and in some cases there are big overlaps.

Another interesting thing about NET markers is that an undiagnosed patient may undergo several specialist tests to eliminate the many possibilities that are being presented as vague and common symptoms.  Sometimes this is necessary to eliminate or ‘home in’ on a tumour type or syndrome/hormone involved (it’s that jigsaw thing again!).

Markers too can be divided into broad categories, those measuring how much tumour is in your body and its growth potential and those measuring how functional (or not) those tumours are.  The latter can probably be expanded to measure/assess excess hormone secretion and syndromes.

The Anatomy

Certain tests can be anatomy related so to add context and to prevent big repetitive lists when using the terms ‘foregut’, ‘midgut’ and ‘hindgut’, you may find this graphic useful.

foregut midgut hindgut

Markers for measuring Tumour bulk or load/growth prediction

Chromogranin (plasma/blood test)

cgaChromogranin is an acidic protein released along with catecholamines from chromaffin cells and nerve terminals. This statement alone might explain why it is a good marker to use with NETs.  Depending on the test kit being used, you may see test results for Chromogranin A (CgA) and Chromogranin B (CgB) – the inclusion of CgB tends to be confined to Europe. There is also mention of Chromogranin C (CgC) in places but I’ve never heard of this being used in conjunction with NETs.

One of the disadvantages of CgA is that the results can be skewed by those taking Proton Pump Inhibitors (PPIs).  Many NET patients are taking PPIs to treat GERD (….and Zollinger-Ellison Syndrome). In the long-term, this has the result of increasing gastrin levels which can lead to an increase of CgA in the blood including for some months after discontinuing. CgB is said not be as influenced by the use of PPI as CgA. In addition to the issue with PPIs, CgA levels may also be elevated in other illnesses including severe hypertension and renal insufficiency. CgB is also said to be more sensitive to Pheochromocytoma.

Elevated CgA is a constant and somewhat excitable discussion point on patient forums and not just because of the lack of unit of measurement use I discussed above. Some people get quite excited about a single test result.  I refer to Dr Woltering et al (ISI Book) where it clearly states that changes in CgA levels of more than 25% over baseline are considered significant and a trend in serial CgA levels over time has been proven to be a useful predictor of tumour growth (i.e. a single test result with an insignificant rise may not be important on its own).  Dr Woltering also gives good advice on marker tests when he says “normal is normal” (i.e. an increased result which is still in range is normal).

Here is a nice graphic explaining what else could be the cause of elevated CgA:

causes-of-cga-elevated

CgA appears to be a widely used tumour marker and is effective in most NETs (foregut, midgut and hindgut). It is also sensitive to Pheochromocytoma, particularly when correlated with a 131I-MIBG scan. Interestingly Chromogranin can also be used in the immunohistochemical staining of NET biopsy samples (along with other methods).

As for my own experience, my CgA was only elevated at diagnosis, remained elevated after intestinal surgery but returned to normal after liver surgery (indicating the effect of liver tumour bulk on results).  It also spiked out of range when some growth in a distant left axillary node was reported in Jan 2012.  Following a lymphadenectomy, it returned to normal again and has remained in range to this day.  It has been a good predictor of tumour bulk for me and I’m currently tested every 6 months.

Pancreastatin

In effect, this marker does the same job as CgA.  Interestingly, Pancreastatin is actually a fragment of the CgA molecule. There have been many studies (mainly in the US) indicating this is a more efficient marker than CgA, and not only because it is not influenced by the use of PPI.  It has also been suggested that it’s more sensitive than CgA and therefore capable of detecting early increases in tumour burden. It has also been suggested it can be an indication of tumour ‘activity’ (whatever that means). It is widely used in the US and some physicians will use it in preference to CgA (…..although from what I read, CgA also seems to be tested alongside).  I’m starting to see this mentioned in the UK.

Neurokinin A (NKA)

This is not a well publicised test. However, it is something used in USA but I’d like to hear from others to validate its use elsewhere.  In a nutshell, this test, which only applies to well differentiated midgut NETs, appears to have some prognostic indication.  I discovered this test in the ISI NET Guidance and it’s backed up by a study authored by names such as Woltering, O’Dorisio, Vinik, et al.  This is not a one-off test but one designed to be taken serially, i.e. a number of consecutive tests.  These authors believe that NKA can also aid in the early identification of patients with more aggressive tumors, allowing for better clinical management of these patients.  NKA is sometimes called Substance K.

Neuron-Specific Enolase (NSE)

In patients with suspected NET who have no clear elevations in the primary tumor markers used to diagnose these conditions, an elevated serum NSE level supports the clinical suspicion.

Markers for measuring Tumour functionality/hormone/peptide levels

So far, I’ve covered basic tumor markers which have a tumor bulk and/or prognostic indication.  This section is a slightly more complex area and many more tests are involved. There’s often a correlation between CgA/Pancreastatin and these type of markers in many patients i.e. a serial high level of CgA might indicate a high level of tumour bulk and therefore increased production of a hormone in patients with a syndrome or oversecreting tumor. However, it frequently does not work out like that, particularly when dealing with non-functioning tumours.

The type of marker for this element of NET diagnosis and surveillance will vary depending on the type of NET and its location (to a certain extent).  Like tumour bulk/growth, there might be different options or test variants on an international basis. There are too many to list here, so I’ll only cover the most common.

Serotonin Secreting Tumors

There are a few markers in use for measuring the functionality of this grouping of tumours. This tumour group has a tendency to secrete excess amounts of the hormone Serotonin although it differs depending on the area of the primary. For example, hindgut tumours tend to secret lower levels than foregut and midgut and therefore this test may present within range.  Please also note there may be other hormones of note involved. The antiquated and misleading term ‘Carcinoid’ is sometimes used as a descriptor for these tumours and more and more NET scientific organisations and specialists are now avoiding use of this term.

lug-the-jug
Lug the Jug

5HIAA.  5HIAA is a metabolite of Serotonin thus why it’s a useful thing to measure to assess functionality in this grouping of tumours. 5HIAA is actually the ‘gold standard’ test for functioning serotonin secreting tumours. It’s a key measure of the effects of carcinoid syndrome and the risk of succumbing to carcinoid heart disease.  However, there are two methods of testing:  Urine and Plasma. The latter is mainly used in USA but other countries are now looking at implementing the plasma version (in fact I’m now tested in both at my local hospital in UK).  The rather obvious key difference between the two is practicality. With the 24 hour urine, there are two key issues: 1.  The logistics (i.e. lug the jug).  2.  Fasting for up to 3 days prior to the test (4 if you count the day of the test). There are numerous variations on the fasting theme but most labs tend to say not to eat at least the following foods that contain high levels of serotonin producing amines: avocados, bananas, chocolate, kiwi fruit, pineapple, plums, tomatoes, and walnuts.  Some lists contain additional items. With the plasma version, the fasting period is reduced to 8 hours. There are also medicinal limitations including drugs that can also alter 5-HIAA urine values, such as acetanilide, phenacetin, glyceryl guaiacolate (found in many cough syrups), methocarbamol, and reserpine. Drugs that can decrease urinary 5-HIAA levels include heparin, isoniazid, levodopa, monoamine oxidase inhibitors, methenamine, methyldopa, phenothiazines, and tricyclic antidepressants. Patients should talk to their doctor before decreasing or discontinuing any medications.

As for my own experience, my 5HIAA (urine) was elevated at diagnosis only returning to normal after removal of my primary and commencement of Lanreotide. It has been a good measure of tumour functionality for me and I’m currently tested every 6 months.

Other tests for the tumour subgroup include but not limited to:

Serum Serotonin (5-HydroxyTryptamine; 5-HT).  Firstly let’s deconflict between 5HIAA above and the serotonin (5-HT) blood test.  5HIAA is a metabolite of serotonin but the serotonin test is a measure of pure serotonin in the blood.  Morning specimens are preferred and this is a fasting test (10-12 hours).  There is always debate on forums about Serum Serotonin results.  I have Dr Liu on record as saying “a high serotonin level measured in the blood in isolation really isn’t that dangerous. It’s the 5HIAA (a breakdown product of serotonin, which is easily measured in the blood and urine) that is considered to be more indicative of persistent elevated hormone. It’s this test that is most closely related to the carcinoid heart disease”.

Substance P.   A substance associated with foregut and midgut tumours.  It is a vasoactive protein that can cause wheezing, diarrhea, tachycardia, flushing

Histamines – Usually associated with foregut tumors. Appears to be involved in patchy rashes and flushing.  The advice in the ISI NET book is no anti-histamine medication to be taken for 48 hours prior to blood draw.

Gastric NETs (Stomach)

Testing will be different depending on the Type:

  • Type 1 – Typical Low Grade, tends to be caused by atrophic gastritis.
  • Type 2 – Atypical Intermediate Grade and tends to be caused by gastrin secreting tumours.  Type 2 normally needs a check for MEN1/Zollinger-Ellison Syndrome.
  • Type 3 – Tend to be larger and more aggressive tumours.

The key makers are CgA and Gastrin although Gastrin may not be elevated in Type 3. Gastrin ph is useful to differentiate between Type 1 and Type 2.  5HIAA can be considered but Carcinoid Syndrome is rare in Gastric NETs.

NETs of the Pancreas (pNETs)

pancreatic-cells
There are many different types of cells in the pancreas

pNETs can be very difficult to diagnose and not only because they share some presentational similarities to their exocrine counterparts.  Some pNETs actually comprise tumours arising in the upper part of the duodenum (small intestine) close to the Pancreas. Moreover, more than half of pNETs are non-functional which increases the difficulty in suspecting and then finding the tumours.  However, where there is clinical presentation or suspicion, these symptoms can lead to the appropriate testing to support the output of scans. The fasting gut profile mentioned above can be useful in identifying the offending hormones when the type of NET is not yet known.

Gut Hormones (Glucagon, Gastrin, VIP, Somatostatin, Pancreatic Polypeptide)

A gut hormone screen is used for the diagnosis of a variety of endocrine tumours of the pancreas area. Analysis includes gastrin, VIP, somatostatin, pancreatic polypeptide, and glucagon, but there may be others depending on processes used by your ordering specialist or hospital.

Notes:

1. You may see this referred to as a ‘Fasting Gut Profile’ or a ‘Fasting Gut Hormone Profile’.

2.  The individual hormones measured seem to differ between hospital labs.

3.  The fasting conditions also vary between hospitals and labs but all agree the conditions are critical to the most accurate results. Always ask for instructions if you’re offered this test.

The gastrin test is usually requested to help detect high levels of gastrin and stomach acid. It is used to help diagnose gastrin-producing tumours called gastrinomas, Zollinger-Ellison (ZE) syndrome, and hyperplasia of G-cells, specialised cells in the stomach that produce gastrin. It may be measured to screen for the presence of multiple endocrine neoplasia type I (MEN) It may be used if a person has abdominal pain, diarrhoea, and recurrent peptic ulcers. A gastrin test may also be requested to look for recurrence of disease following surgical removal of a gastrinoma.

Vasoactive intestinal peptide (VIP) measurement is required for diagnosis of pancreatic tumour or a ganglioneuroma which secretes VIP. Administration of VIP to animals causes hyperglycaemia, inhibition of gastric acid, secretion of pancreatic bicarbonate and of small intestinal juice, and a lowering of systemic blood pressure with skin flush. These features are seen in patients with a tumour of this type which is secreting VIP.

Glucagon is measured for preoperative diagnosis of a glucagon-producing tumour of the pancreas in patients with diabetes and a characteristic skin rash (necrolytic migratory erythema).

Pancreatic polypeptide (PP) production is most commonly associated with tumours producing vasoactive intestinal polypeptide and with carcinoid syndrome and, less commonly, with insulinomas and gastrinomas.

When secreted by endocrine tumours, somatostatin appears to produce symptoms similar to those seen on pharmacological administration, i.e. steatorrhoea, diabetes mellitus and gall stones.

There are several types of pNETs, each with their own syndrome or hormone issue.  When they are suspected due to the presentational symptoms, the markers that could be used are listed below.  These types of tumours are complex and can be related to one or more syndromes.  A patient may be tested using multiple markers to include or exclude these.  Depending on other factors, some physicians may recommend additional marker testing in addition to the most common types below.

Insulinoma – Insulin, Proinsulin, C-peptide

Gastrinoma– Gastrin, Gastrin pH

Glucagonoma – Glucagon, Insulin, Pancreatic Polypeptide (PP), Adrenocorticotropic hormone (ACTH)

VIPoma – Vasoactive Intestinal Polypeptide (VIP), Electrolytes (due to profuse diarrhea)

Somatostatinoma – Somatostatin (plasma somatostatin like immunoreactivity)

PPoma – Pancreatic Polypeptide (PP)

Other NETs/Syndromes

Pheochromocytoma/Paraganglioma – Adrenaline-producing tumours. Plasma and urine catecholamines, plasma free total metanephrines, urine total metanephrines, vanillylmandelic acid (VMA)

Medullary Thyroid Cancer. Medullary thyroid cancer (MTC) starts as a growth of abnormal cancer cells within the thyroid – the parafollicular C cells. In the hereditary form of medullary thyroid cancer (~20% of cases, often called Familial MTC or FMTC), the growth of these cells is due to a mutation in the RET gene which was inherited. This mutated gene may first produce a premalignant condition called C cell hyperplasia. The parafollicular C cells of the thyroid begin to have unregulated growth. In the inherited forms of medullary thyroid cancer, the growing C cells may form a bump or nodule in any portion of the thyroid gland.  Unlike papillary and follicular thyroid cancers, which arise from thyroid hormone-producing cells, medullary thyroid cancer originates in the parafollicular cells (also called C cells) of the thyroid. These cancer cells make a different hormone called calcitonin, which has nothing to do with the control of metabolism in the way  thyroid hormone does.  The other test often seen in MTC is Carcinoembryonic Antigen (CEA). CEA is a protein that is usually found in the blood at a very low level but might rise in certain cancers, such as medullary thyroid cancer. There is no direct relationship between serum calcitonin levels and extent of medullary thyroid cancer.  However, trending serum calcitonin and CEA levels can be a useful tool for doctors to consider in determining the pace of change of a patient’s medullary cancer.

[please note there are extremely rare occurrences of elevated calcitonin from places outside the thyroid – read more here.

Parathyroid– Parathyroid hormone (PTH), Serum Calcium.  Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low.  A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1 – see MEN below.

Pituitary/Cushings – Adrenocorticotropic hormone (ACTH), Cortisol.

HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands.

Adrenocorticotropic hormone (ACTH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ACTH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ACTH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ACTH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ACTH may be due to:

Cushing’s disease – this is the most common cause of increased ACTH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ACTH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.

Cortisol

This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome.  Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.

Other hormones related to ACC include:

Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.

Estrogen – early signs of puberty in children, enlarged breast tissue in males.

Aldosterone – weight gain, high blood pressure.

Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.

A tumour outside the pituitary gland, producing ACTH (also called ectopic ACTH). With NETs, this is normally a pNET, Lung/Bronchial NET or Pheochromocytoma.

Multiple Endocrine Neoplasia (MEN).  Please note MEN is a group of distinct syndrome not a tumor.  Complex area and tends to be multiple instances of some of the tumours above.  For a breakdown of MEN types and locations, check out my MEN blog ‘Running in the Family’

Carcinoid Heart Disease(CHD) (Hedinger syndrome)  I’m not really talking directly about a tumour here but thought it would be useful to include a blood test called NT-proBNP.  I’ve left a link to my CHD article in the paragraph heading for those who wish to learn more about CHD in general.  For those not offered an annual Echocardiogram or are ‘non-syndromic’ there is a screening test that can give an indication of any heart issue which might then need further checks.

The Future – Molecular Markers?

This is testing using DNA and genes.  Exciting but complex – check out this article which involved some NETs.

Tumour Markers and Hormone levels – complex subject!

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Neuroendocrine Cancer Syndromes – Early Signs of a Late Diagnosis

Early signs of a late diagnosis (2)One of the curious things about Neuroendocrine Cancer (NETs going forward) is that it can very often exhibit one or more vague symptoms collectively known as a ‘syndrome’.  Syndrome is an apt word to describe these complications as the most general meaning in medical terms is a group of symptoms that together are characteristic of a specific disorder or disease”.  Having a syndrome can often be the difference between having a ‘functional’ condition or a non-functional’ condition – see more below.

This frequently makes Neuroendocrine Cancer very difficult to diagnose quickly.  It’s a very devious disease.

It’s not all about Carcinoid Syndrome!

Most people think of Carcinoid Syndrome when they discuss NETs. Anyone suggesting that all NET patients get carcinoid syndrome or that all symptoms of NETs are caused by carcinoid syndrome, is WAY off the mark. Firstly, not everyone will have a ‘syndrome’ in addition to their tumours – the percentage is actually well below 50%. Secondly, there are in actual fact, several associated syndromes depending on the anatomical location and type of NET. As an example of one syndrome, statistics vary from source to source but it is estimated that around a 30-45% of all ‘midgut’ patients will present with metastatic disease and around a third of those (∼10-15% of all midgut) will exhibit Carcinoid Syndrome indicating their tumours are ‘functional’ (secreting excess hormones, particularly serotonin).  It follows that Carcinoid Syndrome itself is not that common and it could be the same with other types of NET (even though it can appear more prevalent on forums).

Diagnostic Challenges in NETs (this graphic only covers so-called Carcinoid Syndrome).  Inner segments are the key symptoms, outer segments are some of the potential misdiagnosis/delayed diagnosis. Graphic courtesy of Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128: 1717-1751

Functional / Non-Functional

These tumours and associated syndromes are treatable for most but the difficult part can be arriving at a diagnosis. Moreover, without a syndrome, some of these tumours can be silently growing and as they grow slowly, the ‘silence’ can go on for some years. Even with a syndrome, the root cause can remain disguised as the symptoms are similar to many day-to-day illnesses, again the reason for the title of this blog. Curiously, the lack of a syndrome can sometimes lead to an even later presentation and the consequences that arise (i.e. no signs to aid a diagnosis). In fact a large proportion of Pancreatic NETs are non-functional at diagnosis. There can be the odd exception but in general terms, NETs are either functional (with a syndrome) or non-functional (no syndrome). It’s also possible that patients can move from one state to another.

It’s useful to know about the range of tumor markers and hormone markers – read more here

Syndrome and Tumors – ‘Chicken or Egg’ ?

I’m always confused when someone says they have been diagnosed with a Syndrome rather than a NET type.  You normally need a tumor to produce the symptoms of a syndrome.

The exception might be hereditary syndromes e.g. MEN.  MEN syndromes are genetic conditions. This means that the cancer risk and other features of MEN can be passed from generation to generation in a family. A mutation (alteration) in the various MEN genes gives a person an increased risk of developing endocrine/neuroendocrine tumors and other symptoms of MEN. It’s also possible that the tumors will be discovered first.  It’s complex!

Major NET Syndromes  

(information mainly taken from the ISI Book on NETs with a cross-reference from ENETS and UKINETS Guidelines)

The ISI Book on Neuroendocrine Tumors 2016 (Woltering et al) confirms there are a number of syndromes associated directly and indirectly with NETs and are described as individual syndromes according to their secretory hormones and peptides. The reference publication expands on this list to aid diagnoses by including common presentations, associated tumour types and locations and the offending secreting hormones. You can see why Neuroendocrine Cancer is a diagnostic challenge!

Carcinoid – a syndrome connected with (mainly) serotonin secreting tumours in certain locations (mainly small intestine, lung, stomach, appendix, rectum). The key symptoms include diarrhoea, flushing of the skin (particularly the face), stomach cramping, heart problems such as palpitations, and wheezing. The syndrome is actually caused by the release of a number of hormones, in particular Serotonin, Bradykinin, Tachykinin (Substance P), Histamine, and Prostaglandins.

(there’s also a very rare instance of pancreatic based tumours producing carcinoid syndrome effects – according to ENETs less than 1% of all tumours associated with carcinoid syndrome)

Whipple’s Triad – Whipple’s Triad is the classic description of insulinoma which includes symptoms of hypoglycemia with a low blood glucose concentration relieved by the ingestion of glucose. These tumours can be located anywhere within the pancreas in the cells that make insulin. Insulin is a hormone that controls the amount of  glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. Some of these tumours will be associated with MEN1 syndrome.

Zollinger-Ellinson SyndromeA tumour that forms in cells that make gastrin and can be known as a Gastrinoma. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas.  This is a condition in which one or more tumours form in the pancreas, the upper part of the duodenum or the stomach (these organs are very close and tightly packed together). These tumours secrete large amounts of the hormone gastrin, which causes your stomach to produce too much acid. The excess acid can lead to peptic ulcers, in addition to diarrhea and other symptoms.  Associated with Gastrinoma (pNET) and Gastric NETs.  Some of these tumours may be associated with MEN1 syndrome.

Werner-Morrison SyndromeVasoactive Intestinal Peptide (VIP) is secreted thus the pNET term – VIPoma –  Sometimes the syndrome is referred as WDHA – Watery Diarrhea, Hypokalemia (potassium deficiency), and Achlorhydria (absence of hydrochloric acid in gastric secretions).  Sometimes known as Pancreatic Cholera. Some of these tumours may be associated with MEN1 syndrome

Glucagonoma.  A tumour that forms in cells that make make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar) rendering most patients diabetic. A glucagonoma usually forms in the tail of the pancreas.  Some of these tumours may be associated with MEN1 syndrome.  See also Sweet’s Syndrome below.  Sometimes known as the 4D syndrome – Dermatological, Diabetes, DVT, Depression.

Somatostatinoma is a very rare type of NET, with an incidence of one in 40 million persons. These tumours produce excess somatostatin arise from the delta cells in the pancreas, although these cells can also be present in duodenal/jejunum tissue where around 44% of these tumours occur. Somatostatin is a naturally occurring peptide that inhibits the function of almost all gut hormones (author’s note – this fact should give you an appreciation of how somatostatin analogues tackle associated syndromes whilst giving you certain side effects as a result!)

Pancreatic Polypeptide (PP)PPoma A complicated one and not too much information (even in the ISI book or ENETS Guidelines). However, it’s the third most common type of islet cell tumour (i.e. pNET).  The function of pancreatic polypeptide is not completely understood. Patients present with weight loss, jaundice, and abdominal pain. The diagnosis is confirmed by pancreatic polypeptide levels > 300 pg/ml. Some of these tumours may be associated with MEN1 syndrome.

Hedinger Syndrome – the technical name for Carcinoid Heart Disease and an ideal replacement term now that Carcinoid is being phased out.

Cushing’s – also known as hypercortisolism.  A collection of symptoms caused by very high levels of a hormone called cortisol in the body.   In Cushing’s disease, oversecretion of pituitary ACTH induces bilateral adrenal hyperplasia. This results in excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone. Cushing’s disease, a subset of Cushing’s syndrome, is due to a pituitary corticotroph adenoma and results in a partial resistance to the suppression of ACTH by cortisol so that secretion is unrestrained. In contrast, causes of Cushing’s syndrome may include the following:

•   Adrenal adenoma or carcinoma arise spontaneously. ACTH levels are undetectable.

•   Non-pituitary (ectopic) tumours produce ACTH. They most frequently originate in the thorax and are highly aggressive small cell carcinomas of the lung or slow- growing bronchial or thymic carcinoid tumours. Some produce corticotropin- releasing hormone (CRH) instead, which stimulates pituitary ACTH secretion and can therefore mimic a pituitary tumour.

•   Other causes include NETs of the gastric, pancreatic, and intestinal organs; Pheochromocytomas, and MCT.

The hallmark of Cushing’s syndrome is that ACTH levels are partially resistant to suppression with dexamethasone, even at very high doses. Some MEN patients with pituitary tumours may have Cushing’s Syndrome. AdrenoCorticoTropic Hormone (ACTH) releasing tumours are somerimes known as ACTHoma.

Sweet’s – Dermatitis/rash associated with Glucagonomas.  Not to be confused with Pellagra (B3 deficiency)

Neuroendocrine / Endocrine tumors can be seen in several inherited familial syndromes, including but not limited to:

  • Multiple Endocrine Neoplasia type 1 (MEN1)
  • Multiple Endocrine Neoplasia type 2 (MEN2)
  • Multiple Endocrine Neoplasia type 4 (MEN4)
  • SDHx mutations – Hereditary Pheochromocytoma/Paraganglioma Syndromes.
  • Pituitary.
  • Von Hippel-Lindau (VHL) Disease
  • Neurofibromatosis Type 1 (also known as Recklinghausen’s Disease). Not covered further.
  • Tuberous Sclerosis (not covered further)
  • Carney Complex

see Genetics and Neuroendocrine Tumors

MEN1 – Mainly involved the 3 Ps, Pituitary, Pancreas and Parathyroid.  The pituitary tumours are primarily Prolactinomas, the pancreatic tumours are mainly PPomas, Gastrinomas and Insulinoma.  Many also have association with Zollinger-Ellinson  syndrome (ZES).  Sometimes known as Wermer Syndrome.  Associated with the MEN1 gene.

MEN2A – associated with the RET gene, can result in Medullary Thyroid Carcinoma, Pheochromocytoma, and overactive parathyroid glands characterised by a high calcium level.

MEN2B. An inherited disorder characterised by the certain development of Medullary Thyroid Carcinoma, plus the possible development of pheochromocytomas and characteristic tumours (mucosal neuromas) of the lips, tongue and bowels. Parathyroid disease is extremely rare in MEN2B.  Also connected with the RET gene.

MEN4.  A relatively new MEN variant and related to the CDKN1B gene.  Similar to MEN1 but normally only 2 of the 3 Ps, parathyroid and pituitary; and potentially other places.

SDHx mutations/Hereditary pheochromocytoma/paraganglioma syndromes

  • Succinate dehydrogenase (SDH) is an enzyme which is important for the metabolic function of mitochondria. Patients with mutations of these genes have increased risk of pheochromocytomas, paragangliomas, stomach tumors and kidney tumors.
  • SDHx mutations (SDHA, SDHB, SDHC, and SDHD) can present as Pheochromocytomas/Paragangliomas and other non-NET conditions.  If this interests you see site http://www.SDHcancer.org

Von Hippel-Lindau (VHL) – not an exclusively NET syndrome. VHL is a rare disorder caused by a faulty gene. It is named after the two doctors who first described the disease, and affects about one in 35,000 people. Tumours develop in one or more parts of the body. Many of these tumours involve the abnormal growth of blood vessels in parts of the body which are particularly rich in blood vessels. Areas most frequently affected are the eyes, the back of the brain (cerebellum), the spinal cord, the kidneys, the adrenal glands and the pancreas. People are affected differently, even within the same family. The only VHL tumour which tends to run in families affects the adrenal glands (Pheochromocytoma). Different VHL features tend to develop at different ages. The eye angiomas often develop in childhood. Others, including tumours found in the cerebellum, spinal cord or adrenal glands (Haemangioblastomas and Pheochromocytomas) can develop from late childhood onwards. The kidney tumours are usually the last things that develop, from the mid-twenties onwards.  Most VHL related tumours are benign.

Summary

As for my own experience of syndromes, I did once show symptoms of the most common NET syndrome (currently known as Carcinoid syndrome) where the key symptoms include diarrhoea, flushing of the skin (particularly the face), stomach cramping, heart problems such as palpitations, and wheezing.  You can see why those symptoms are frequently and easily confused with other conditions. If you have a similar diagnosis, you may benefit from looking at something known as The 5 E’s which is a useful list of things to be wary of.

I did have issues for a year or two in 2010 leading up to diagnosis and until my treatment was underway.  I was experiencing flushing and infrequent bouts of diarrhea but I totally ignored it (hear me talk about this). However, it ended up being instrumental in my diagnosis albeit some good luck was involved in getting to that point.  My twist of fate which involved a low hemoglobin score led me to a scan and ‘bingo’.  I had a ‘gastrointestinal blip’ some 18 months previously but that proved colonoscopy negative.  Despite my distant and metastatic tumour disposition and seemingly late diagnosis, I’m current non-syndromic due to “early” intervention and good treatment.  However, my ongoing treatment continues to play its part.

For many, the vague and routine symptoms generated by a syndrome contribute to the fact that NET Cancer is frequently misdiagnosed with some people suffering from the side effects for many years before a correct diagnosis is made.

There are many other less known syndromes that appear to be directly or indirectly connected with Neuroendocrine Tumours and I may update this post if I discover they are more prevalent than I think.  Please let me know if you’ve been told you have a NET related syndrome not listed.

Neuroendocrine Cancer – shh! Can you hear it? 

Thanks for reading

Ronny

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Neuroendocrine Cancer – Hormones

HormonesNET 2018

Until I was diagnosed with metastatic Neuroendocrine Cancer, I didn’t have a clue about hormones – it’s one of those things you just take for granted. However, hormones are vital to human health (male and female) and it’s only when things go wrong you suddenly appreciate how important they are ……..like a lot of other things in life I suppose! The presence of over-secreting hormones (often called peptides throughout) is useful to aid diagnosis albeit it often means the tumours have metastasized. It’s also a frequent indication that the person has an associated NET syndrome.

This is a really complex area and to understand the hormone problems associated with Neuroendocrine Cancer, you need to have a basic knowledge of the endocrine and neuroendocrine systems.  I’ve no intention of explaining that (!) – other than the following high level summary:

  • Glands in the endocrine system use the bloodstream to monitor the body’s internal environment and to communicate with each other through substances called hormones, which are released into the bloodstream.  Endocrine glands include; Pituitary, Hypothalmus, Thymus, Pineal, Testes, Ovaries Thyroid, Adrenal, Parathyroid, Pancreas.
  • A Hormone is a chemical that is made by specialist cells, usually within an endocrine gland, and it is released into the bloodstream to send a message to another part of the body. It is often referred to as a ‘chemical messenger’. In the human body, hormones are used for two types of communication. The first is for communication between two endocrine glands, where one gland releases a hormone which stimulates another target gland to change the levels of hormones that it is releasing. The second is between an endocrine gland and a target organ, for example when the pancreas releases insulin which causes muscle and fat cells to take up glucose from the bloodstream. Hormones affect many physiological activities including growth, metabolism, appetite, puberty and fertility.
  • The Endocrine system. The complex interplay between the glands, hormones and other target organs is referred to as the endocrine system.
  • The Neuroendocrine System. The diffuse neuroendocrine system is made up of neuroendocrine cells scattered throughout the body.  These cells receive neuronal input and, as a consequence of this input, release hormones to the blood. In this way they bring about an integration between the nervous system and the endocrine system (i.e. Neuroendocrine).  A complex area but one example of what this means is the adrenal gland releasing adrenaline to the blood when the body prepares for the ‘fight or flight’ response in times of stress, ie, for vigorous and/or sudden action.

Hormones – The NET Effect

Hormones – the NET Effect

At least one or more hormones will be involved at various sites and even within certain syndromes, the dominant and offending hormone may differ between anatomical tumour sites. For example, NETs of the small intestine, lung or appendix (and one or two other places) may overproduce serotonin and other hormones which can cause a characteristic collection of symptoms currently called carcinoid syndrome.   The key symptoms are flushing, diarrhea and general abdominal pain, loss of appetite, fast heart rate and shortness of breath and wheezing. The main symptom for me was facial flushing and this was instrumental in my eventual diagnosis. The fact that I was syndromic at the point of diagnosis made it easier to discover, albeit the trigger for the investigation was a fairly innocuous event.  Other types of NETs are also affected by the overproduction of hormones including Insulinomas, Gastrinomas, Glucagonomas, VIPomas, Somatostatinomas, and others.  These can cause their own syndromes and are not part of carcinoid syndrome as some organisations incorrectly state. For more on NET syndromes – Read Here.

So are hormones horrible? 

Absolutely not, they are essential to the normal function of the human body.  For example if you didn’t have any of the hormone Serotonin in your system, you would become extremely ill.  On the other hand, if your glands start secreting too much of certain hormones, your body could become dysfunctional and in some scenarios, this situation could become life threatening.  So hormones are good as long as the balance is correct. NET patients with an oversecreting tumor may be classed as “functional”.

  • Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
  • Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows. Many NET patients are deemed to be “non-functioning” with normal hormone levels. It’s also accurate to say that many can move from one stage to the other.

Location Location Location

It’s accurate to say that the type and amount of hormone secretion differs between locations or sites of the functional tumor and this can also create different effects.  The division of NETs into larger anatomical regions appears to differ depending on where you look but they all look something likes this:

Foregut NETs: In the respiratory tract, thymus, stomach, duodenum, and pancreas. This group mostly lack the enzyme aromatic amino decarboxylase that converts 5-HTP (5-Hydroxytryptophan – a precursor to serotonin) to serotonin (5-HT); such tumours tend to produce 5-HTP and histamine instead of serotonin.  The Pancreas is a particularly prominent endocrine organ and can produce a number of different syndromes each with their associated hormone oversecretion – although many can be non-functional (at least to begin with). Lung NETs rarely produce serotonin, but may instead secrete histamine causing an ‘atypical’ carcinoid syndrome with generalized flushing, diarrhea, periorbital oedema, lacrimation and asthma. They may also produce adrenocorticotropic hormone (ATCH) or corticotropin-releasing factor (CRP), resulting in an ectopic Cushing’s syndrome. Please note the respiratory tract and thymus are not really anatomically pure ‘Foregut’ – but in NETs, grouped there for convenience. 

Midgut NETs: In the small intestine, appendix, and ascending colon. For example, serotonin secreting tumors tend to be associated with carcinoid syndrome which tends to be associated with midgut NETs and this is normally the case. Many texts will also tell you that a syndrome only occurs at a metastatic stage.  Both are a good rule of thumb but both are technically incorrect. For example, ovarian NETs can have a form of carcinoid syndrome without liver metastasis (tends to be described as atypical carcinoid syndrome). It’s also possible to see serotonin secreting tumors in places such as the pancreas (although what you would call that type of NET is open for debate).

Hindgut NETs (transverse, descending colon and rectum) cannot convert tryptophan to serotonin and other metabolites and therefore rarely cause carcinoid syndrome even if they metastasise to the liver.

Less Common Locations – there are quite a few less common NET locations which may involve less common hormones – some are covered below including the key glands contributing to NETs.

Unknown Primary? –  One clue to finding the primary might be by isolating an offending hormone causing symptoms.

The key NET hormones

Serotonin

I used the example of Serotonin above because it is the most cited problem with NET Cancer although it does tend to be most prevalent in midgut tumors. Serotonin is a monoamine neurotransmitter synthesized from Tryptophan, one of the eight essential amino acids (defined as those that cannot be made in the body and therefore must be obtained from food or supplements). About 90% of serotonin produced in the body is found in the enterochromaffin cells of the gastrointestinal (GI) tract where it is used mainly to regulate intestinal movements amongst other functions. The remainder is synthesized in the central nervous system where it mainly regulates mood, appetite, and sleep. Please note there is no transfer of serotonin across the blood-brain barrier.

Alterations in tryptophan metabolism may account for many symptoms that accompany carcinoid syndrome. Serotonin in particular is the most likely cause of many features of carcinoid syndrome as it stimulates intestinal motility and secretion and inhibits intestinal absorption. Serotonin may also stimulate fibroblast growth and fibrogenesis and may thus account for peritoneal and valvular fibrosis encountered in such tumours; serotonin, however, it is said not to be associated with flushing. The diversion of tryptophan to serotonin may lead to tryptophan deficiency as it becomes unavailable for nicotinic acid synthesis, and is associated with reduced protein synthesis and hypoalbuminaemia; this may lead to the development of pellagra (skin rash, glossitis, stomatitis, confusion/dementia).

Serotonin is also thought to be responsible for ‘right sided’ heart disease (Carcinoid Heart Disease). It is thought that high levels of serotonin in the blood stream damages the heart, leading to lesions which cause fibrosis, particularly of the heart valves. This generally affects the right side of the heart when liver metastases are present. The left side of the heart is usually not affected because the lungs can break down serotonin. Right sided heart failure symptoms include swelling (edema) in the extremities and enlargement of the heart.

Whilst serotonin can be measured directly in the blood, it’s said to be more accurate to measure 5HIAA (the output of serotonin) via blood or urine, the latter is said to be the most accurate.

Tachykinins

Tackykinins include Substance P, Neurokinin A, Neuropeptide K and others. They are active in the enterochromaffin cells of the GI tract but can also be found in lung, appendiceal and ovarian NETs, and also in Medullary Thyroid Carcinoma and Pheochromocytomas. They are thought to be involved in flushing and diarrhea in midgut NETs. The most common tachykinin is Substance P, which is a potent vasodilator (substances which open up blood vessels). Telangiectasias are collections of tiny blood vessels which can develop superficially on the faces of people who have had NETs for several years. They are most commonly found on the nose or upper lip and are purplish in color. They are thought to be due to chronic vasodilatation.

Histamine

Histamine is a hormone that is chemically similar to the hormones serotonin, epinephrine, and norepinephrine. After being made, the hormone is stored in a number of cells (e.g., mast cells, basophils, enterochromaffin cells). Normally, there is a low level of histamine circulating in the body. However (and as we all know!), the release of histamine can be triggered by an event such as an insect bite. Histamine causes the inconvenient redness, swelling and itching associated with the bite. For those with severe allergies, the sudden and more generalized release of histamine can be fatal (e.g., anaphylactic shock). Mast cell histamine has an important role in the reaction of the immune system to the presence of a compound to which the body has developed an allergy. When released from mast cells in a reaction to a material to which the immune system is allergic, the hormone causes blood vessels to increase in diameter (e.g., vasodilation) and to become more permeable to the passage of fluid across the vessel wall. These effects are apparent as a runny nose, sneezing, and watery eyes. Other symptoms can include itching, burning and swelling in the skin, headaches, plugged sinuses, stomach cramps, and diarrhea. Histamine can also be released into the lungs, where it causes the air passages to become constricted rather than dilated. This response occurs in an attempt to keep the offending allergenic particles from being inhaled. Unfortunately, this also makes breathing difficult. An example of such an effect of histamine occurs in asthma. Histamine has also been shown to function as a neurotransmitter (a chemical that facilitates the transmission of impulses from one neural cell to an adjacent neural cell).

In cases of an extreme allergic reaction, adrenaline is administered to eliminate histamine from the body. For minor allergic reactions, symptoms can sometimes be lessened by the use of antihistamines that block the binding of histamine to a receptor molecule.  Histamine is thought to be involved with certain types and locations of NET, including Lung and foregut NETs where they can cause pulmonary obstruction, atypical flush and hormone syndromes.

Histamine, another amine produced by certain NETs (particularly foregut), may be associated with an atypical flushing and pruritus; increased histamine production may account for the increased frequency of duodenal ulcers observed in these tumours.

Kallikrein

Kallikrein is a potent vasodilator and may account for the flushing and increased intestinal mobility.

Prostaglandins

Although prostaglandins are overproduced in midgut tumours, their role in the development of the symptoms of carcinoid syndrome is not well established but triggering peristalsis is mentioned in some texts.

Bradykinin

Bradykinin acts as a blood vessel dilator. Dilation of blood vessels can lead to a rapid heartbeat (tachycardia) and a drop in blood pressure (hypotension). Dilation of blood vessels may also be partly responsible for the flushing associated with carcinoid syndrome.

Gastrin

Gastrin is a hormone that is produced by ‘G’ cells in the lining of the stomach and upper small intestine. During a meal, gastrin stimulates the stomach to release gastric acid. This allows the stomach to break down proteins swallowed as food and absorb certain vitamins. It also acts as a disinfectant and kills most of the bacteria that enter the stomach with food, minimising the risk of infection within the gut. Gastrin also stimulates growth of the stomach lining and increases the muscle contractions of the gut to aid digestion. Excess gastrin could indicate a NET known as a Gastric NET (stomach) or a pNET known as Gastrinoma (see pancreatic hormones below).

Endocrine Organs

Thyroid Gland

Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland. Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone. This means that it acts to reduce calcium levels in the blood. This hormone tends to involve Medullary Thyroid Carcinoma and Hyperparathyroidism in connection to those with Multiple Endocrine Neoplasia. Worth also pointing out the existence of Calcitonin Gene-Related Peptide (CGRP) which is a member of the calcitonin family of peptides and a potent vasodilator.  Please note that hypothyroidism is often a side effect of NETs or treatment for NETs – please click here to read about the connection.

Pituitary Gland

HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands. However, I’m only covering the pituitary and adrenal due to their strong connection with NETs.

Adrenocorticotropic hormone (ATCH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ATCH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ATCH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ATCH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ATCH may be due to:

Cushing’s disease – this is the most common cause of increased ATCH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ATCH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.

A tumour outside the pituitary gland, producing ATCH is known as an ectopic ATCH. With NETs, this is normally a pNET, Lung/Bronchial/Pulmonary NET or Pheochromocytoma.

Adrenal Glands

Adrenaline and Noradrenline

These are two separate but related hormones and neurotransmitters, known as the ‘Catecholamines’. They are produced in the medulla of the adrenal glands and in some neurons of the central nervous system. They are released into the bloodstream and serve as chemical mediators, and also convey the nerve impulses to various organs. Adrenaline has many different actions depending on the type of cells it is acting upon.  However, the overall effect of adrenaline is to prepare the body for the ‘fight or flight’ response in times of stress, i.e. for vigorous and/or sudden action. Key actions of adrenaline include increasing the heart rate, increasing blood pressure, expanding the air passages of the lungs, enlarging the pupil in the eye, redistributing blood to the muscles and altering the body’s metabolism, so as to maximise blood glucose levels (primarily for the brain). A closely related hormone, noradrenaline, is released mainly from the nerve endings of the sympathetic nervous system (as well as in relatively small amounts from the adrenal medulla). There is a continuous low-level of activity of the sympathetic nervous system resulting in release of noradrenaline into the circulation, but adrenaline release is only increased at times of acute stress.  These hormones are normally related to adrenal and extra adrenal NETs such as Pheochromocytoma and Paraganglioma.  Like serotonin secreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured (amongst other tests) by 24 hour urine test very similar to 5HIAA (with its own diet and drug restrictions).  It’s known as 24-hour urinary catacholamines and metanephrines.  Worth noting that adrenaline is also known as Epinephrine (one of the 5 E’s of Carcinoid Syndrome).

Cortisol

This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome.  Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.

Other hormones related to ACC include:

Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.

Estrogen – early signs of puberty in children, enlarged breast tissue in males.

Aldosterone – weight gain, high blood pressure.

Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.

Parathyroid

Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low.  A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1

Pancreatic Hormones (Syndromes)

Pancreatic neuroendocrine tumors form in hormone-making cells of the pancreas. You may see these described as ‘Islet Cells’ or ‘Islets of Langerhans’ after the scientist who discovered them. Pancreatic NETs may also be functional or non-functional:

  • Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
  • Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows.

There are different kinds of functional pancreatic NETs. Pancreatic NETs make different kinds of hormones such as gastrin, insulin, and glucagon. Functional pancreatic NETs include the following:

  • Gastrinoma: A tumor that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers, and diarrhea are caused by a tumor that makes gastrin, it is called Zollinger-Ellison syndrome. A gastrinoma usually forms in the head of the pancreas and sometimes forms in the small intestine. Most gastrinomas are malignant (cancer).
  • Insulinoma: A tumor that forms in cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. An insulinoma forms in the head, body, or tail of the pancreas. Insulinomas are usually benign (not cancer).
  • Glucagonoma: A tumor that forms in cells that make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas. Most glucagonomas are malignant (cancer).
  • Pancreatic Polypeptide (PPoma). A pancreatic polypeptide is a polypeptide hormone secreted by the pancreatic polypeptide (PP) cells of the islets of Langerhans in the endocrine portion of the pancreas. Its release is triggered in humans by protein-rich meals, fasting, exercise, and acute hypoglycemia and is inhibited by somatostatin and intravenous glucose. The exact biological role of pancreatic polypeptide remains uncertain. Excess PP could indicate a pNET known as PPoma.
  • Other types of tumors: There are other rare types of functional pancreatic NETs that make hormones, including hormones that control the balance of sugar, salt, and water in the body. These tumors include:
  • VIPomas, which make vasoactive intestinal peptide. VIPoma may also be called Verner-Morrison syndrome, pancreatic cholera syndrome, or the WDHA syndrome (Watery Diarrhea, Hypokalemia (low potassium)and Achlorhydria).
  • Somatostatinomas, which make somatostatin. Somatostatin is a hormone produced by many tissues in the body, principally in the nervous and digestive systems. It regulates a wide variety of physiological functions and inhibits the secretion of other hormones, the activity of the gastrointestinal tract and the rapid reproduction of normal and tumour cells. Somatostatin may also act as a neurotransmitter in the nervous system.

The pancreas is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1

Having certain syndromes can increase the risk of pancreatic NETs.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Multiple endocrine neoplasia type 1 (MEN1) syndrome is a risk factor for pancreatic NETs.

Signs and symptoms of pancreatic NETs

Signs or symptoms can be caused by the growth of the tumor and/or by hormones the tumor makes or by other conditions. Some tumors may not cause signs or symptoms. Check with your doctor if you have any of these problems.

Signs and symptoms of a non-functional pancreatic NET

A non-functional pancreatic NET may grow for a long time without causing signs or symptoms. It may grow large or spread to other parts of the body before it causes signs or symptoms, such as:

  • Diarrhea.
  • Indigestion.
  • A lump in the abdomen.
  • Pain in the abdomen or back.
  • Yellowing of the skin and whites of the eyes.

Signs and symptoms of a functional pancreatic NET

The signs and symptoms of a functional pancreatic NET depend on the type of hormone being made.

Too much gastrin may cause:

  • Stomach ulcers that keep coming back.
  • Pain in the abdomen, which may spread to the back. The pain may come and go and it may go away after taking an antacid.
  • The flow of stomach contents back into the esophagus (gastroesophageal reflux).
  • Diarrhea.

Too much insulin may cause:

  • Low blood sugar. This can cause blurred vision, headache, and feeling lightheaded, tired, weak, shaky, nervous, irritable, sweaty, confused, or hungry.
  • Fast heartbeat.

Too much glucagon may cause:

  • Skin rash on the face, stomach, or legs.
  • High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
  • Blood clots. Blood clots in the lung can cause shortness of breath, cough, or pain in the chest. Blood clots in the arm or leg can cause pain, swelling, warmth, or redness of the arm or leg.
  • Diarrhea.
  • Weight loss for no known reason.
  • Sore tongue or sores at the corners of the mouth.

Too much vasoactive intestinal peptide (VIP) may cause:

  • Very large amounts of watery diarrhea.
  • Dehydration. This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness, or feeling tired.
  • Low potassium level in the blood. This can cause muscle weakness, aching, or cramps, numbness and tingling, frequent urination, fast heartbeat, and feeling confused or thirsty.
  • Cramps or pain in the abdomen.
  • Facial flushing.
  • Weight loss for no known reason.

Too much somatostatin may cause:

  • High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
  • Diarrhea.
  • Steatorrhea (very foul-smelling stool that floats).
  • Gallstones.
  • Yellowing of the skin and whites of the eyes.
  • Weight loss for no known reason.

Too much pancreatic polypeptide may cause:

  • belly pain.
  • an enlarged liver.

Testing hormones

Clearly the presenting symptoms will give doctors a clue to the oversecreting hormone (see list above). Excessive secretions or high levels of hormones and other substances can be measured in a number of ways. For example:

Well known tests for the most common types of NET include 5-Hydroxyindoleacetic Acid (5-HIAA) 24 hour urine test which is also measured by a blood draw. Note: -tumor markers can be measured simultaneously e.g. Chromogranin A (CgA) blood test and/or Pancreastatin as there can very often be a correlation between tumour mass and tumour secreting activity. CgA / Pancreastatin is a blood test which measures a protein found in many NET tumour cells. These marker tests are normally associated with tumour mass rather than tumour functionality.

By measuring the level of 5-HIAA in the urine or blood, healthcare providers can calculate the amount of serotonin in the body (5-HIAA is a by-product of serotonin).  5-HIAA test is the most common biochemical test for carcinoid syndrome or the degree of how ‘functional’ tumours are.  If you’ve understood the text above, you can now see why there are dietary and drug restrictions in place prior to the test.

Pancreatic Hormone testing. There are other tests for other hormones and there is a common test which measured the main hormones seen in NETs. It may be called different things in different countries, but in UK, it’s known as a ‘Fasting Gut Hormone Profile‘.

Scratching the surface here so for a comprehensive list of marker tests for NETs, have a read here.

Treatment for Over-secreting Hormones

Of course, reducing tumour bulk through surgery and other treatment modalities, should technically reduce over-secretion (I suspect that doesn’t work for all).  Other treatments may have the dual effect of reducing tumour burden and the effects of hormone oversecretions.

One of the key treatment breakthroughs for many NET cancer patients, is the use of ‘Somatostatin Analogues’ mainly branded as Octreotide (Sandostatin) or Lanreotide (Somatuline). People tend to associate these drugs with serotonin related secretions and tumours but they are in actual fact useful for many others including the pancreatic NETs listed above.  Patients will normally be prescribed these drugs if they are displaying these symptoms but some people may be more avid to the drug than others and this may influence future use and dosages. This is another complex area but I’ll try to describe the importance here in basic terms. Somatostatin is a naturally occurring protein in the human body. It is an inhibitor of various hormones secreted from the endocrine system (some of which were listed above) and it binds with high affinity to the five somatostatin receptors found on secretory endocrine cells. NETs have membranes covered with receptors for somatostatin. However, the naturally occurring Somatostatin has limited clinical use due to its short half-life (<3 min). Therefore, specific somatostatin analogues (synthetic versions) have been developed that bind to tumours and block hormone release. Thus why Octreotide and Lanreotide do a good job of slowing down hormone production, including many of the gut hormones controlling emptying of the stomach and bowel.  It also slows down the release of hormones made by the pancreas, including insulin and digestive enzymes – so there can be side effects including fat malabsorption.

The recent introduction of Telotristat Ethyl (XERMELO) is interesting as that inhibits a precursor to serotonin and reduces diarrhea in those patients where it is not adequately controlled by somatostatin analogues.

Other than the effects of curative or cytoreductive surgery, some NETs may have very specialist drugs for inhibiting the less common hormone types.  This is not an exhaustive list.

Worth also noting that oversecreting hormones can contribute to a phenomenon known as Carcinoid Crisis – read more here.  For catacholamine secreting tumors (Pheochromocytoma/Paraganglioma), this may be known as Intraoperative Hypertensive Crisis

Sorry about the long article – it’s complex and you should always consult your specialist about issues involving hormones, testing for hormones and treating any low or high scores.

Thanks for reading

Ronny

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