Neuroendocrine Cancer: Fibrosis – an unsolved mystery?


Background

It has long been observed that certain Neuroendocrine Tumours (NETs) are often associated with their ability to secrete hormones and these substances are thought to be responsible for the collection of symptoms which include (but not limited to) diarrhea, flushing and wheezing.  One of the lesser known aspects of this disease is the development of fibrosis, both local and distant. These fibrotic complications may lead to considerable morbidity. They can also result in incidental diagnoses of NETs after causing abdominal obstructions.

The most well known form of fibrosis is ‘Hedinger Syndrome’ (so-called Carcinoid Heart Disease) tightly associated with midgut NETs and will not be covered further. However, mesenteric fibrosis is actually more common and also associated with midgut NETs.  There are other less common locations involved including retroperitoneal fibrosis, pleural and pulmonary fibrosis and skin fibrosis.

According to a paper (abstract linked below) by Professor Martyn Caplin (et al) regarding mesenteric fibrosis, “it often has a characteristic appearance of a mesenteric mass with linear soft tissue opacities radiating outward in a “wheel spoke” pattern associated with distortion of the surrounding tissues” (see graphic below).

The mesentery and retroperitoneum areas

The mesentery and retroperitoneum are complex to describe but think of the mesentery as something holding the small intestine together with all its folds and the retroperitoneum describes the part of the abdomen that is generally closer to your backbone than to your belly button, i.e. behind the intestines.

Often labelled ‘Desmoplasia’, it is easily spotted on CT and MRI scans and is one of the unusual features of NETs vs other types of cancer.  Some examples are below:

Desmoplastic-reaction-The-characteristic-desmoplastic-reaction-comprises-a-mesenteric
Desmoplastic reaction. The characteristic desmoplastic reaction comprises a mesenteric mass (black asterisks) with linear soft tissue opacities radiating outwards in a ‘spoke-wheel’ or stellate pattern (black arrows) and associated indrawing of the surrounding tissues . Distortion and retraction of the adjacent soft tissues results in kinking of the small bowel and can cause partial or complete bowel obstruction. The mesenteric mass is often associated with coarse calcification (black arrowhead).  
Metastatic-carcinoid-tumor-to-the-root-of-the-mesentery-arrow-causing-typical
Metastatic Neuroendocrine Tumor to the root of the mesentery (arrow) causing typical circumferential desmoplastic

Axial CT image of a patient with a metastatic neuroendocrine tumor that demonstrates retroperitoneal thickening and fibrosis (arrow).

Small intestinal neuroendocrine tumor with characteristic serosal fibrosis causing kinking of the bowel wall (hematoxylin-eosin, original magnification 3 1; scanned slide) Grin, Andrea & Streutker, Cathy. (2015). Neuroendocrine Tumors of the Luminal Gastrointestinal Tract. Archives of pathology & laboratory medicine. 139. 750-756. 10.5858/arpa.2014-0130-RA.

What causes it, what problems does it cause and how can it be treated?

As with Hedinger Syndrome, which mostly causes right-sided fibrosis in the heart, mesenteric and retroperitoneal fibrosis (and others) is thought to be caused by the excess secretion of serotonin (5-HT) from NETs. I say ‘thought’ but no-one really knows for sure.  There’s a few quite recent studies on the subject which I’ll provide abstracts here.

Uppsala Hospital Sweden. In one study entitled “Clinical signs of fibrosis in small intestinal neuroendocrine tumours” first published in November 2016 by Uppsala Hospital Sweden, it said that it was caused by serotonin and other cytokines released from tumour cells and which may induce fibrosis, leading to carcinoid heart disease and abdominal fibrotic reactions. A cohort study of patients with SI NETs diagnosed between 1985 and 2015 was carried out – a total of 824 patients. Clinically significant abdominal signs and symptoms of fibrosis occurred in 36 patients. Of these, 20 had critically symptomatic central mesenteric fibrosis causing obstruction of mesenteric vessels, and 16 had retroperitoneal fibrosis causing obstructive uropathy with hydronephrosis (the swelling of a kidney due to a build-up of urine).  Extensive fibrosis causing mesenteric vessel obstruction and/or obstructive uropathy was more often associated with symptomatic and advanced disease encompassing lymph node metastases in the mesenteric root, para‐aortic lymph node metastases, as well as liver metastases and peritoneal carcinomatosis. Palliative intervention in terms of superior mesenteric vein stenting or resection of central mesenteric metastases and/or percutaneous nephrostomy and J stent treatment was beneficial in the majority of the patients. They concluded by saying that extensive abdominal fibrosis associated with clinically significant symptoms of intestinal ischaemia and/or obstructive uropathy was linked to advanced disease in patients with SI NETs. Prompt recognition and minimally invasive intervention was effective in disease palliation.

Royal Free Hospital. In another fairly recent paper entitled “Neuroendocrine tumors and fibrosis: An unsolved mystery?”, published by Professor Martyn Caplin of the Royal Free (and others), where this issue is discussed alongside the role of serotonin, growth factors, and other peptides in the development of NET related fibrotic reactions.  They also suggested serotonin as the main culprit in both CHD fibrosis and in mesenteric/retroperitoneum and expressed many of the factors above.  This study suggested that up to 50% of SI NET patients may be involved but looking at both reports together indicates that the first study above only isolated clinically significant cases whereas Royal Free looked for signs in all cases.

Another recent paper (also a paid subscription) from Royal Free (Caplin et al) indicated that the severity of mesenteric desmoplasia did not seem to demonstrate a statistically significant effect on overall survival or long-term outcome (taken from a study of 147 patients at Royal Free London). Sounds like good news but there are clearly consequences that could arise from the issue.

I do not have access to all the texts above, only the abstracts which I’ve linked above (all only available from paid subscriptions).

One older publication authored by known UK NET expert endocrinologist, covered some of the above issues but added that fibrosis in the pleural/pulmonary areas and the skin could also be associated.   For ease of reference, the following extracts are cited to Fibrosis and carcinoid syndrome: from causation to future therapy Maralyn Druce, Andrea Rockall and Ashley B. Grossman Druce M. et al. Nat. Rev. Endocrinol. 5, 276–283 (2009); doi:10.1038/nrendo.2009.51

Mesenteric fibrosis and carcinoid syndrome.  Intestinal fibrosis in a series of 37 patients with jejunoileal carcinoid tumors, 8 of 12 patients with bowel obstructions had evidence of fibrosis or kinking of the bowel.6 among 36 patients with carcinoid syndrome who were seen at Yale university, 15 either had fibrosis at the time of surgery, or developed it subsequently. In a surgical series of 121 patients with midgut carcinoid tumors, 75 required laparotomy, due to abdominal pain; of these patients, 59 were noted to have marked mesenteric fibrosis at the time of surgery. Spread of the primary tumor into the mesentery and peritoneum can result in a marked fibrotic reaction. This fibrosis can mat together multiple loops of bowel and result in kinking, ischemia, volvulus and obstruction.

Retroperitoneal fibrosis. True retroperitoneal fibrosis is a rare clinical entity, in which inflammation results in fibrosis throughout the retroperitoneum. In two-thirds of patients this condition is idiopathic. The majority of cases that are not idiopathic are associated with drugs, such as antihypertensive agents and methysergide. Although retroperitoneal fibrosis is not commonly seen in the context of carcinoid syndrome and has not been reported in any recent, major review, several cases have been reported in literature. 

Pleural and Pulmonary Fibrosis. In a review of 50 patients with carcinoid tumors who presented to a single unit over 9 years and were examined using CT, 14 patients had pleural thickening, and in 9 of these cases no other attributable cause was established. All 14 patients had developed this pleural thickening within 2 years of being diagnosed as having carcinoid syndrome, and 7 of the 9 patients also had fibrosis elsewhere, for example, in the heart valves, skin or mesentery. Carcinoid syndrome has rarely been described as a cause of alveolar fibrosis, but fibrosis elsewhere in the lung occurs more frequently. in a series of 25 patients known to have peripheral carcinoid tumors of the lung, 19 displayed hyperplasia of neuroendocrine cells elsewhere in the lung, and 8 patients (25%) had lesions of obliterative bronchiolitis, including 2 with asymptomatic obstruction of airflow. These data suggest that bronchiolar fibrosis is not uncommon, although it is usually subclinical.

Skin fibrosis. Dermal fibrosis may be primary or secondary to peripheral vasospasm, which occurs in response to vasoconstrictor substances that are secreted by the tumor. Carcinoid syndrome associated with scleroderma has been reported: in one series, its prevalence was 2 cases in 25 individuals. This complication of carcinoid syndrome is usually a late feature and may be attenuated by the use of cyproheptadine hydrochloride, parachlor phenylalanine and prednisolone, which suggests a causative role for tryptophan metabolism and 5-HT”

What happened to me?

Since I was diagnosed in 2010, I’ve always known I’ve had a fibrosis issue in the retroperitoneal area, as it was actually identified on my very first CT Scan, which triggered my diagnosis.  Here’s how the radiologist described it – “There is a rind of abnormal tissue surrounding the aorta extending distally from below the renal vessels. This measures up to 15mm in thickness”.  He went on to describe that “almost certainly malignant”.  The second and third scans would go on to describe as “retroperitoneal fibrosis” and “a plaque like substance”.  Interestingly the fibrosis itself does not appear to ‘light up’ on nuclear scans indicating it was not cancerous (see below).

I really didn’t know what to make of this issue at diagnosis, although I did know the aorta was pretty important!  Fortunately I had a surgeon who had operated on many NET patients and has seen this issue before.  After my first surgery, he described it as a “dense fibrotic retroperitoneal reaction encircling his aorta and cava (inferior vena cava (IVC))”. My surgeon was known for difficult and extreme surgery, so as part of the removal of my primary, he also spent 3 hours dissecting out the retroperitoneal fibrosis surrounding these important blood vessels and managed 270 degree clearance. The remnant still shows on CT scans. Some of the removed tissue was tested and found to be benign, showing only florid inflammation and fibrosis (thankfully).  That said, the abstract papers above has led me to believe that my retroperitoneal fibrosis is clinically significant.

Routine surveillance in 2018 has picked up that retroperitoneal fibrosis is potentially impinging on important vessels in this area, particularly the left ureter but including some blood vessels. A follow up Ga68 PET confirms active lymph nodes in the retroperitoneal area that might be contributing to continued or new fibrosis growth.

In order to further assess risk to my kidneys, I had a different nuclear can known as a Renal MAG3. This scan looks at the blood supply, function and flow of urine from the kidneys. The output will inform my MDT and surgical team looking at treatment options to counter the risk of damage and the timing of potential surgery to correct the issue. I’m happy to report that the MAG3 scan confirmed there are no blockages to my kidneys or bladder. It did confirm my right kidney is doing 60% of the work, the suspected left one is covering the remaining 40% effort.  Apparently it’s pretty normal that it isn’t exactly 50/50.  Surgery is now on the back burner (phew!).  The kidney function will be monitored closely going forward.

Summary

These issues need to be identified early on in diagnostics, preventative treatment considered and then monitored going forward.  Potential complications may include (but not be limited to) bowel and blood vessel obstructions.  Retroperitoneal fibrosis also needs to be monitored as potential complications may include (but not be limited to) obstructive uropathy.

For those worried about this issue, please note that when you look at the statistics from Uppsala, only 4.5% of cases are classed as clinically significant and with the retroperitoneal area, the figure reduces to 2%.

Neuroendocrine Cancer is normally slow growing BUT …..

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Update: Management of Neuroendocrine Tumors

This is an excellent and positive video based overview of where we are with the Management of NETs.  This is a presentation from a NET Specialist (who some of you may know) presenting to a “GI Malignancies” conference.  This is therefore not only awareness of NETs, it’s also some good education for non NET GI experts who may only know the very basics. Useful for patients too!  I met Dr Strosberg in Barcelona (ENETS 2017) and thanked him for his presentational and scientific paper output which I often use in my articles.

The classification picture is good as it explains the different facets of NETs and how NETs are classified and categorised in a general way – not seen it done this way before.   Slightly out of date as it does not adequately convey the possibility of a well differentiated high grade recently classified by the World Health Organisation – read more here.

Amazingly it is delivered without using the word ‘carcinoid’ other than in reference to syndrome, indicating it can be done and is something also being reflected in all my posts to ensure they are up to date with the latest nomenclature.  It’s also a good example for GI doctors as this branch of medicine is often involved in NET diagnostics and surveillance.

Excellent update of all the trials which have introduced treatments in the last decade.

Screenshot 2017-12-12 16.34.54

Great update and worth the 30 minutes it takes to watch – you can view it CLICK HERE.

 

 

All graphics courtesy of www.oncologytube.com

Thanks for reading

Ronny

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Neuroendocrine Cancer – normally slow but always sneaky?

 

cancer cells attack

There’s a lot of scary diseases in this world but some of them are particularly spooky.  One such spooky disease is the lesser known type of cancer that infiltrated my body – Neuroendocrine Cancer (aka Neuroendocrine Tumors or NET for short).  Not only is it scary and spooky, but it’s also cunning, devious, misleading, double-crossing, and it likes nothing better than to play tricks on you.

It will grow in your body without you knowing.  It finds places to hide, mainly the small intestine, appendix, lungs, stomach, pancreas, rectum and a host of other places. It can be fiendishly small to avoid being seen.  Once it’s established in the primary location (….or locations), it will try to break out via your blood and lymphatic systems.  It wants to establish other bases in your mesentery, your liver, your lymph nodes, your bones and any other place it can get to.

It can often be uncannily quiet, not showing any symptoms. However, sometimes it wants to have fun by over-secreting certain hormones to add or introduce symptoms which mimic many other diseases such as IBS, asthma, abdominal upset, diarrhea, flushing. These are just more tricks up its sleeve.  You will go to your doctor, perhaps many times, to report what looks like routine/regular symptoms. Unfortunately, it’s also really good at tricking your doctors. After several visits and despite your concerns, your doctors could become so frustrated that nothing serious is obvious, they might even start to think it’s all in your head. This is exactly what Neuroendocrine Cancer wants, it’s just getting started.

One particular type of NET has a wicked trick up its sleeve.  This one will over-secrete a hormone called Serotonin which can often cause fibrosis in your abdominal area, potentially causing obstructions and damage to major organs and blood vessels.  It’s not finished though, it will also try to introduce fibrosis to the right side of your heart causing more life threatening issues. In addition to common symptoms of flushing, this type and others will also make you feel weak, fatigued, pain, agitated, anxious, dizzy, nauseous, jaundiced, acid reflux, skin irritation, anemic, lose weight and give you heart palpitations.  It’s a real Witch’s Brew of symptoms and living with it is often not easy.  Its main trick is to prevent you from being correctly diagnosed and it’s pretty good at it.

However, it has a ‘finale’ trick.  Neuroendocrine Cancer actually wants to kill you, and if it’s left to plough its relentless path throughout your body, that’s exactly what it will do, slowly but surely. 

It’s not just slow and scary, it can also be deadly. Spread the word and help save a life.

If you are suspicious you have Neuroendocrine Cancer but not yet formally diagnosed, you may appreciate this article.

Thanks for reading

Ronny

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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!

tt

Serotonin – the NET effect

A team of researchers from Case Western Reserve University School of Medicine have used high-powered microscopes for the first time to view serotonin activating its receptor

Background

I’d never heard of Serotonin until I was diagnosed with Neuroendocrine Cancer in 2010.  It is frequently discussed, often with contrasting views from the respondents. One common assumption/question is that it is responsible for many things that can go wrong with Neuroendocrine Cancer patients who have serotonin-producing tumours. “It’s the hormones” is an easy assumption to make or an easy answer to give in response to a complex set of circumstances.  It’s difficult to get a definitive answer and the science behind the behaviour of our hormones isn’t really 100% tied down.

You may see serotonin referred to as a ‘neurotransmitter’, a ‘chemical’ and a ‘hormone’ – this is complex but it is my understanding that it can add context in respect the role/location of the serotonin, e.g. chemical and hormone are essentially synonymous and are endocrine related whereas neurotransmitter is concerned with the nervous system (the neuro in neuroendocrine) and the brain (more on this below). Consequently, I’ll keep this as basic as I can (author’s note on completion – it was not easy!).

Serotonin and NETs

One thing which is widely accepted and agreed…… Serotonin is definitely involved in Neuroendocrine Tumours, in particular, those resulting in carcinoid syndrome which can manifest as a number of symptoms including but not limited to flushing and diarrhea.  Although serotonin is one of the main ‘hormones’ released in excess by certain NETs (mainly midgut), it is not thought to be the main culprit behind some of the symptoms produced by Carcinoid Syndrome.  For example, flushing, the most common symptom (and a cardinal one) is thought to be caused by a number of hormones/peptides – too many to list but the main ones are histamine (particularly foregut), tachykinins (Substance P), bradykinins, prostaglandins …….. and I’m sure serotonin’s in there too!  It does, however, appear to be massively guilty in causing carcinoid syndrome diarrhoea, desmoplasia, and carcinoid heart issues.

Where does Serotonin come from?

Serotonin’s technical name is 5-hydroxyltryptamine (5-HT).  It is converted from 5-Hydrotryptophan (5-HTP) which is also known as oxitriptan. 5-HTP is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of serotonin (…..and melatonin) from tryptophan. Tryptophan is interesting as that brings in one of the missing pieces of the jigsaw – food!  Tryptophan cannot be manufactured in the body, it must be brought in via diet. There is no serotonin in food, it is only manufactured in the body.

Tryptophan in food enters the body and serotonin is created by a biochemical conversion process which combines tryptophan (essentially a protein) with tryptophan hydroxylase (TPH), a chemical reactor. I suspect other substances might be involved in that process.  There are two forms of tryptophan hydroxylase – TPH1 and TPH2, which are encoded on two independent genes. TPH1 is linked to peripheral serotonin while TPH2 is related to brain serotonin.

While serotonin cannot cross the blood-brain barrier, tryptophan can, and almost all of it is converted to serotonin. Just to emphasise that NET dietitians do not say to avoid foods containing tryptophan other than at the time of marker testing (see below and nutrition Blog 4).

Are you happy with your serotonin?

Serotonin Inhibitors

The introduction of Somatostatin analogues (SSAs) such as Octreotide and Lanreotide, help reduce the secretion of “tumour-derived serotonin”  by binding to its receptors on the outside of the cell.  If you ever wondered why receptors are important, please check out my blog on this subject (click here).

I mentioned tryptophan hydroxylase (TPH) above and that is actually very interesting as this is how Telotristat Ethyl (XERMELO) is able to help with the symptoms of Carcinoid Syndrome diarrhea (not adequately controlled by SSAs) or where patients are unable to be treated by somatostatin analogues for whatever reason. It’s a potent inhibitor of TPH which will disrupt the manufacturing of tumour-derived serotonin. There is also evidence that it can help reduce the effects or halt the growth of the fibrosis leading to carcinoid heart disease.  Slight digression but useful to aid/enhance understanding at this point.  Read about Telotristat Ethyl here.

Serotonin and the Brain

There is constant discussion and assumption that serotonin-producing tumours are somehow causing depression, anxiety and rage.  Not as simple as that, it’s way more complicated.  Certain NETs can overproduce serotonin in the gut but the issues concerning depression and anxiety are normally associated with low levels of serotonin in the brain.

Cancer anger” is a normal response to fear, despair and grief – a range of feelings which cancer brings into our lives. It can show as frustration, irritability, emotional withdrawal or aggression. You can feel it whether you have been diagnosed or you are a relative or friend. Cancer anger can happen at any stage of the illness, even years after treatment.

I know many people with cancer who suffer from depression, anxiety and rage but they do not have serotonin-producing tumours.  What they do have is a life threatening and/or life changing condition which is bound to have an effect on mind as well as body.  Serotonin is a natural substance found in the body and not just there to service NETs.  If you didn’t have any, you wouldn’t be able to get out of bed according to one of my ‘favs’ Dr Gene Woltering.

Serotonin is separately manufactured in the brain (~10%) and in the gastrointestinal tract (~90%).  The serotonin in the brain must be manufactured in the brain, it cannot be directly increased or reduced external to the brain, i.e. it cannot be directly reinforced by gut serotonin (peripheral serotonin). It follows that ‘brain serotonin’ and ‘gut serotonin’ are held in separate stores, they are manufactured in those stores and remain in those stores – there is no cross-pollination. This is managed by something called the blood-brain-barrier (BBB). Therefore, excess serotonin from NETs does not infiltrate the brain. As low-level of ‘brain serotonin’ is often linked to depression, it also follows that it’s possible to have high levels of serotonin in the gut but low levels in the brain.

My simple way of thinking about such things as outlined above, is that low levels of tryptophan in the brain might be contributing to low levels of serotonin in the brain.  To clarify that, I researched the reasons why there could be low serotonin in the brain.

First, let’s dismiss any connection that the type of anti-depressant is called Selective serotonin reuptake inhibitors (SSRIs) is involved. It’s thought that SSRIs work by increasing serotonin levels in the brain. Serotonin is a neurotransmitter (a messenger chemical that carries signals between nerve cells in the brain). We already discussed that it’s thought to have a good influence on mood, emotion and sleep. After carrying a message, serotonin is usually reabsorbed by the nerve cells (known as “reuptake”). SSRIs work by blocking (“inhibiting”) reuptake, meaning more serotonin is available to pass further messages between nearby nerve cells. So tryptophan or peripheral serotonin are not really involved.

It would be too simplistic to say that depression and related mental health conditions are caused by low serotonin levels (in the brain), but a rise in serotonin levels (in the brain) can improve symptoms and make people more responsive to other types of treatment, such as Cognitive Behaviour Therapy (CBT).

It should also be noted that the precursor to serotonin, tryptophan, does pass through the BBB and it is therefore possible that tryptophan depletion can lead to less availability in the brain for the manufacture of brain serotonin.  Tryptophan depletion can be caused by dietary restrictions (i.e. lack of tryptophan foods) and also by the effects of certain types of tumours as excess serotonin is made leading to less availability of tryptophan.  Both could lead to low serotonin in the brain as less tryptophan gets there.

Measuring Serotonin levels

Measuring levels of serotonin is important in both diagnosis and management of certain NETs – although it’s probably sensible to test all potential NET patients during diagnosis when the type of tumour is not yet known.  Testing for tumour markers will differ between countries and within countries but the most common standard for testing Serotonin appears to be 5-HIAA (5-hydroxyindoleacetic acid) either via a 24-hour urine test or via a plasma version (mainly used in USA but now creeping into UK).  5-HIAA is the output (metabolite) of 5-HT (Serotonin). Not to be confused with the less reliable ‘serum serotonin’ which is a different test.

Another frequently asked question about serotonin tests is whether they are testing the amount in the brain or the gut. The answer is …… they are testing the levels in the blood. Furthermore, if you are measuring serotonin as an indicator for Carcinoid Syndrome, it has to be remembered that the majority of serotonin is in the gut, so even if serotonin levels in the brain were being measured alongside the gut levels, I don’t believe it would  influence the result in any significant way (but I have no science to back that up). It also has to be remembered that serum serotonin and 5HIAA are not absolute tests, they are not 100% sensitive, they are simply indicators of a potential problem. There are methods of measuring brain serotonin but it is very complex and beyond the purposes of this article.  However, I would just add that it is the reuptake of Serotonin in the brain (plus some other stuff) that can cause depression, not the actual level or amount in the brain.

I intentionally did not mention the other common test (Chromogranin A) or other markers as they are measuring different things but you can read about in my Testing for Markers blog.

Summary

I did say it was a difficult jigsaw!

Thanks for reading

Ronny

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The 5 E’s (of Carcinoid Syndrome)

Guidance and Risk Management
Guidance and Risk Management

Since my diagnosis, I seem to have been in a perpetual learning phase!  What not to do, what not to eat, what not to read!  However, a couple of years ago, I came across a list of ‘E’ words (5 of them) which is a handy reminder for Carcinoid Syndrome patients, particularly those whose symptoms are not under control.  When I say “carcinoid syndrome” in this article, I only mean the syndrome that is caused by what was once called “Carcinoid Tumors”, i.e. mainly serotonin secreting types but include tumours which are well differentiated found in the small intestine, appendiceal, rectal, lung, and one or two other less common places.

There are many variations of this list but this is my take!  I suspect some of this also applies to other types of NETs and other NET Syndromes.

On analysis of this list, it struck me that I was aware of the issues and their potential effects and I’m certain there is science to substantiate the content. These E’s are apparently the most common ‘triggers’ for Carcinoid Syndrome.  Clearly, they are not going to have the same effect on every patient e.g. I have the occasional drink of ‘Ethanol’ and I always enjoy it, I go for long exhausting walks and I always feel great after.  I had dental treatment without any precautions before I was aware of the risks …….. nothing happened!  Before I was treated, stressful meetings at work would make me flush though!  As for eating – well that’s another couple of blog’s worth!   (see the Diarrhea Jigsaw and Nutrition Blog 4 – Food for Thought)

The 5 Es are, however, very important, as a severe attack of Carcinoid Syndrome symptoms could be debilitating and life-threatening and I’m fairly certain the list was compiled with this in mind.  Some people are more affected by Carcinoid Syndrome and this is not necessarily related to the extent or aggressiveness of their disease.  Some people just react differently.  An extremely severe attack of Carcinoid Syndrome can also be known as a ‘Carcinoid Crisis’ which is very dangerous on the operating table due to the effects of anaesthetics  – thus why many NET patients may be infused with somatostatin analogues (usually Octreotide) prior to and during surgery or other medical procedures.  There’s a lot of excitement generated around the term ‘Carcinoid Crisis’ but it is generally uncommon.

I’m not saying the 5Es should be ignored but NET Cancer is complex and most things need to be read in the correct context. What works for some may not work for others. There can also be confusion surrounding the source of symptoms, i.e. are they syndrome or something else?  This is why I believe NET patients need to answer some key questions when considering the risks associated with the 5 E’s:

  • Are you currently syndromic?   If you are, then the 5 ‘E’ list is probably very good advice but interpreting the advice in the correct context remains important.
  • Are your syndrome related biochemistry results normal (e.g. 5HIAA)? Normal readings (in range) tend to mean the syndrome is under control and many people who were diagnosed with a syndrome may actually be non-syndromic following treatment.
  • Have you had treatment or are having treatment likely to produce side effects which might be confused with Carcinoid syndrome? For example, surgery can be the long term cause of diarrhea and other issues. Despite the role of somatostatin analogues, these could also be the root cause of certain reactions.
  • Do you have any other illnesses?  If yes, do these other illnesses produce effects similar to carcinoid syndrome? e.g. asthma, diabetes, rosacea, thyroid disorders, vitamin & mineral deficiencies, malabsorption, gut bacterial imbalance.  Sorting out the symptoms can be a jigsaw with a missing piece sometimes.

The vagaries of this disease will no doubt throw up some exceptions and additions. There will be patients who have no syndrome but have elevated biochemistry and vice versa!  Additionally, there will be patients who have had surgery and/or are being treated with somatostatin analogues but will still be syndromic in varying degrees of severity.

The so-called ‘5 Es’ are as follows:

Epinephrine: This was a new piece of information for me and I only discovered this as a potential problem when I started monitoring some of the USA Facebook forums.  This does not appear to be that well-known in UK. Epinephrine (commonly known as adrenaline) is often used in dentistry mixed with a local anaesthetic. I won’t risk this, so I’ve instructed my Dentist to place a note on my record asking for epinephrine not be used (and clearly I’ll remind them each visit!). According to NET guru Dr Woltering, plain novocaine, carbocaine or plain marcaine are preferred.  You should also check that your anaesthetist for any procedure you may be undergoing is aware of your carcinoid syndrome. However, the danger is not just with dentistry work.  Any anaesthesia is risky.  Check out my post ‘carcinoid crisis’.

For those who have standby ‘Epi Pens’, I did read the following statement on the Carcinoid Cancer Foundation website:  “ …….. one exception is the administration of epinephrine in the case of an allergic anaphylactic reaction (i.e. a bee sting), so it cannot be avoided in this case, just make sure that Octreotide (Sandostatin) is also available“.  This advice is also extremely relevant to Pheochromocytoma and Paraganglioma patients who may be a high risk of intraoperative hypertensive crisis.

Eating: This is very individual.  Certain foods or large meals can be difficult, particularly if you have had any gastrointestinal surgeries. I keep a personal diary trying to identify things that upset my system. I try to find some balance between what I know is good for me and also what I know I enjoy. For example, I found that very large meals do not agree with my ‘new plumbing’. If I eat a lot of sweets, I’ll also suffer …..so I just eat a little – check out my  blog post Chocolate – The NET Effect.

Personally speaking, I’m fairly certain the vast majority of my issues are related to my treatment (past and present) rather than being provoked by Carcinoid Syndrome, i.e. if I rush to the toilet after a meal, it’s not syndrome, it’s a reaction of my compromised digestive system. So with this in mind, I try to reduce those things but additionally strike a balance between quality of life and excessive and rigid adherence to some of the guidance out there (see below) – as I said above, interpretation and context is important. My compromised system cannot deal with big meals so I ‘graze’ most of the day and then eat a small to medium-sized meal in the evening. I’ve been doing this for 3 years and reduced my visits by 300% without any special or expensive medication.

In my blog Nutrition Blog 4 – Food for Thought, I’ve linked to authoritative sources on potential diet triggers.  I’m not suggesting you cut out all of the foods on these lists (you won’t last long!). Some can indulge in those foods and some cannot. For example, chocolate and caffeine (tea/coffee) are on the lists but I eat/drink those frequently (in moderation) and have no problem. It’s a case of testing things out.  I like to describe my eating as ‘The Risk Management of my Quality of Life’. By the way, no-one is suggesting that a NET patient with carcinoid syndrome (and don’t forget this is only one syndrome of many with NETs) should stop eating foods high in the offending amines or are precursors to serotonin (e.g. tryptophan).  They do not make tumours grow (a myth) but just make sure you adhere to the dietary restrictions for any 5HIAA test.

Emotions:  Stressful situations can cause symptoms to flare up. While it is difficult to avoid all stress (work, home, commuting, etc), it is helpful if you can manage or reduce it. Like eating, this is a very individual area. From personal experience, I know stress can exacerbate carcinoid syndrome. Before I started my treatment, I was regularly flushing in meetings at work (….. think boxing matches!). After my treatment, stress was definitely a factor causing increased bowel motility.  I’ve removed a lot of stress from my life and it helps. You may need to be ruthless in managing this aspect of your illness.

Exercise:  Exercise is extremely important for overall health and well-being and I know quite a lot of NET Cancer patients who exercise regularly without issues. It can, however, trigger carcinoid syndrome if you overdo it – it is, however, like eating, a very individual thing. I take the view that ‘zero’ exercise might potentially be an even higher risk. Even a walk around the garden or gardening is exercise. When I was at work, I would walk to see people rather than phone them. Sometimes I walk to town rather than drive, it all adds up! I have evidence from my own exercising regime proving in my case that exercise can reduce the knock-on effects of some of the other E’s (emotions and eating) and/or the side effects of treatment – check out my blog entitled Exercise is Medicine.  Those who are syndromic and/or have other conditions to manage are probably best to take medical advice on how much exercise they need to do.

Ethanol (alcohol, liquor): Many NET patients have difficulty tolerating wine, beer and spirits (hard liquor). I was never a big drinker so for me it was easy to go almost teetotal. I do have the occasional beer but very infrequently and normally on holiday – I personally don’t get any issues with the odd beer but again this is trial and error.  I really enjoy my beer when I celebrate my Cancerversaries. Also check out my blog Alcohol – the NET Effect

Summary

I’m sure there could be a 5 A’s to 5 Z’s list of things to avoid but as I said above, this needs to be balanced with what the actual risks for you are and if you’re like me, quality of life. If you read most Facebook closed group or forums, you will always find at least one person is affected by something which affects no-one else. Please note this article is just my own appreciation of these issues and I emphasise once again that everyone has different experiences. I do, however, think it’s important to consider any secondary illnesses, effects of surgery and biochemistry results (or indeed a combination of one or more of these factors). Everything in life involves some kind of risk management and if you are totally risk averse, then you are unlikely to have much of a life (or a diet!).

It’s not easy but my daily diary helps me assess trends and work out what things upset me more than others – I can then reduce or eliminate. You need to tailor your own advice perhaps with the help of a doctor and/or dietician versed in NET Cancer.  I also have some related posts on the subject of vitamin and mineral deficiencies, malabsorption and probiotics – check them out as the problems associated with these subjects could potentially look like a worsening of carcinoid syndrome and lead to unnecessary worry and unnecessary treatment.

For most, Carcinoid Syndrome can normally be controlled by the use of debulking surgery and/or somatostatin analogues (Octreotide/Lanreotide).  However, there is a new drug called ‘Teloristat Ethyl’ (XERMELO) which looks like it may provide supplementary treatment for patients whose carcinoid syndrome diarrhea is not adequately controlled by somatostatin analogues. It’s an expensive drug and comes with side effects so you need to be sure it’s your syndrome causing the problem before you commit to a prescription.

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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Telotristat Ethyl (XERMELO®) – an oral treatment for Carcinoid Syndrome Diarrhea not adequately controlled by Somatostatin Analogues

Telotristat Ethyl is an extremely significant introduction to the treatment of Carcinoid Syndrome diarrhea. It’s the first addition to the standard of care in more than 16 years and the first time an oral syndrome treatment has been developed.  The drug was previously known as Telotristat Etiprate but was changed to Ethyl in Oct 2016. ‘Etiprate’ was previously a truncation of ‘ethyl hippurate’.  The brand name is XERMELO® 

UPDATE MARCH 2018 

The March 2018 issue of Clinical Therapeutics provides the first report of the effects of XERMELO on changes in weight in patients with neuroendocrine tumors (NETs) and carcinoid syndrome that participated in the TELESTAR study. You have to remember that XERMELO is approved for those with carcinoid syndrome diarrhea not adequately controlled by somatostatin analogues (author’s note – i.e not for diarrhea caused by (say) side effects of surgery).

Of the 120 patients with weight data available, up to 32.5% of patients treated with XERMELO experienced significant, dose-dependent weight gain (≥3% from baseline). Only 5.1% of patients on placebo experienced weight gain. Importantly, patients with weight gain experienced improvement in carcinoid syndrome control, as seen in reduction of bowel movement frequency and in parameters of nutritional status associated with positive changes in patient-reported outcomes compared with patients with stable weight or weight loss. Those patients also experienced reduced u5-HIAA levels. Patients with weight gain also experienced fewer serious adverse events than patients with stable weight or weight loss.

(see link below)

Who is the drug for?

The drug may be of benefit to those whose carcinoid syndrome diarrhea is not adequately controlled by somatostatin analogues (Octreotide/Lanreotide). It doesn’t replace somatostatin analogues – it is an additional treatment alongside (although I have heard of patients in the US being subscribed who are not receiving somatostatin analogue treatment)

Where is it currently approved?

The US FDA approved the drug 28 February 2017.

On 19 September 2017,the European Commission approved Xermelo® (telotristat ethyl) for the treatment of carcinoid syndrome diarrhea in patients inadequately controlled by somatostatin analogue therapy after the scientific committee of the EMA (known as Committee for Medicinal Products for Human Use (CHMP)) adopted a positive opinion recommending the approval of Xermelo® (telotristat ethyl) 250 mg three times a day for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy. The Ipsen press release is here.  Clearly some action will be required in EC national countries before the drug becomes available through the appropriate healthcare systems.


On 17 Oct 2018, Health Canada announced approval for Canadian NET patients – click here.

For all other countries please note that Ipsen will pursue a worldwide regulatory plan for marketing authorisation submissions in the territories in which it operates. Once approved, Ipsen will be distributing the drug in all countries less USA and Japan where Lexicon retains the rights. Outside USA and Europe will be constrained by national approval timelines.

How does it work?

In the simplest of terms, the drug is an inhibitor of the enzyme tryptophan hydroxylase (TPH).  TPH is the rate-limiting enzyme in serotonin synthesis which converts tryptophan (an essential amino acid which comes from diet) to 5-hydroxytryptophan, which is subsequently converted to serotonin, one of the main causes of carcinoid syndrome effects including carcinoid heart disease.  The trial data indicates that Telotristat ethyl significantly reduced the frequency of bowel movements. Furthermore, it was also associated with “significantly reduced levels of urinary 5-HIAA“, a marker for systemic serotonin levels, which are typically elevated in severe carcinoid syndrome.  Essentially it works by reducing the manufacture of Serotonin so it’s it may not have any effect on diarrhea not caused by syndrome (i.e. post surgery etc).

telotristat-etiprate-clinical-trial-serotonin-as-a-key-driver-of-carcinoid-syndrome

Resources for your perusal:

  • You can read more about the trial data in a summary by Dr Matthew Kulke (Dana Farber) by CLICKING HERE (latest review from 2017 ASCO).
  • There is also an excellent summary in video form by Dr Lowell Anthony (University of Kentucky) by CLICKING HERE. (“any reduction in diarrhea is meaningful“).
  • The detailed output from the trial (results) can be found by CLICKING HERE.
  • Great 2016 article from ASCO (American Society of Clinical Oncologists) can be found by CLICKING HERE.
  • FDA Approval.  CLICK HERE
  • Lex Pharma press release on approval.  CLICK HERE
  • EU Approval (Ipsen Press Release).  CLICK HERE
  • The manufacturer Lex Pharma have established a dedicated site – CLICK HERE
  • 2018 revised clinical data – CLICK HERE

Thanks for reading

Ronny

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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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Carcinoid – What’s in a name?


The Other C word

A quick primer on the word ‘CARCINOID‘.  It originates from the term ‘Carcinoma-like’.  ‘CARCIN’ is a truncation of Carcinoma (by definition cancerous or malignant tumour). ‘OID’ is a suffix meaning ‘resembling’ or ‘like’.  This infers that Carcinoid cannot be a truly malignant tumour – thus the confusion (….. and anger!). The most worrying connotation of the use of the word ‘Carcinoid’ is the belief that they all have benign clinical and biological behaviour.  That is dangerous thinking which could end up killing people.

There is now widespread use of the term Neuroendocrine Tumours (NETs) and this is based on the latest classification scheme pushed out by the World Health Organisation (WHO) in 2010 subsequently updated by WHO 2017.  The correct term for all types is actually Neuroendocrine Neoplasm (NEN) which is an umbralla term for all well differentiated tumours (NETs) and poorly differentiated carcinomas (NEC).  I’ll use NET going forward as that is where the confusion lies.

However, ‘Carcinoid’ seems to prevail in many parts of social media, advocate organisations, patients, even doctors are out of date. As a blogger and social media geek, I still use it as it’s a popular search phrase (although I’m always careful with context and in the correct ‘scenario’).  However and unfortunately, some still use it as a synonym for all NETs which is clearly incorrect. So called Carcinoid was ever only one type of NET albeit covering more than one location. I’m therefore baffled by the continued and frequent use of phrases such as “Carcinoid and Neuroendocrine Tumours” which misleadingly infers they are different cancers. Not helpful.

To prevent confusion, the use of the term NETs frequently needs to be expanded to distinguish between the different types. However, there does not appear to be any agreement on the naming conventions and I suspect this is probably one of the reasons why many people (including NET Specialists and advocate organisations) continue to use the term Carcinoid. I’ve seen sporadic use of the term SINET (small intestinal NET) and SB NET (small bowel NET) and we already have pNET (notice the syntax difference …..) and more recently I’ve seen ‘PanNET’.  I believe use of the anatomy has potential as a way forward but we need consistency.  Check out my article below entitled Carcinoid vs Neuroendocrine for advice on the correct terminology to use.

The primary NET is really important for context and understanding, thus why many patient advocate organsiation and cancer sites will still classify and list ‘Carcinoid’ as a single NET type rather than the long list of anatomical locations which can no longer be grouped under the heading of the Carcinoid type.  There are also many other factors involved and no solution seems to be perfect up to this point.  As for syndromes, there are several. So patients confused by the ‘instruction’ on the use of ‘Carcinoid’ will just say “I have the syndrome”. Just which one are they talking about? We also need to consider Carcinoid Heart Disease and Carcinoid Crisis and I have excellent suggestions for renaming both.

Another term I regularly see is ‘Noid’ – a truncation of Carcinoid.  Whilst I suspect that might have been popular and convenient 20 years ago, clearly it is not helpful when you consider the issues above.  Personally speaking, I find myself annoyed by being described as a Noid! Particularly when the ‘oid‘ part is what is causing the angst described above.  And while we’re at it, I’m also annoyed by being described as a zebra, that is another thing holding up our 21st century awareness campaigns.  Let’s move out of the 1980s please!

Some might say all of the above is just semantics and it’s nothing to get too excited about.  However, I believe we need more coordinated awareness and more coordinated clout for Neuroendocrine disease.  We should at least be consistent with the nomenclature messages (amongst other things).

You’ll find updated thinking in my other post “Carcinoid vs Neuroendocrine”

Fortunately the big NET specialist organisations are slowly getting rid of the word ‘Carcinoid’ and this is long overdue.  It will take a while and patients can set the example for the doctors and medical writers.

carcinoid falling out of favor

Ignore this post about Neuroendocrine Cancer


ignore-this-post

When I was diagnosed, I wasn’t feeling ill. In hindsight, I now know some of the signs were there, I just put up with them. Neuroendocrine Cancer had laid a trap for me and I fell right into it. You see, Neuroendocrine Cancer can be very quiet and unobtrusive. It also plays the ‘long game’ and will sometimes take years before it’s finally discovered.  It is very very very sneaky.

Not satisfied with loitering in your small intestine, appendix, lungs, stomach, pancreas and a host of other places, it wants to reach out to your liver, your lymph nodes, your bones, bung you up with fibrosis, and get into your heart where it can cause the most damage. It will also try to get into your head, metaphorically speaking – however, it will also try the physical route.

As it spreads, it can become noisier through growth but also by secreting excess amounts of hormones and other substances. It knows that tumour growth and these excess hormones and substances will mimic routine illnesses such as IBS, diarrhea, stool changes including steatorrhoea, stomach cramps and bloating, asthma, facial flushing, menopause, weight loss, anaemia, fatigue, tachycardia (fast heart beat), pain, and nausea – a real witch’s brew of symptoms. These may manifest themselves as common endocrine conditions e.g. it can mess with your blood sugar and thyroid levels.  These are a few examples, there can be many others – it’s a real witch’s brew of symptoms. Neuroendocrine Cancer thinks this is great because it fools doctors into misdiagnosing you with something else which means it can continue to grow undetected and unfettered, spreading further inside you.

If nothing is done to stop its relentless growth, it will eventually kill.

However, sometimes an inquisitive doctor or nurse upsets its progress by thinking ‘outside the box’. Neuroendocrine Cancer hates when people are aware of its devious nature and hates when people know which tests can be used to find it and which treatments are best to attack it. Inquisitive, proactive and determined patients can also add to this effect and sometimes a bit of luck is involved.

It doesn’t give up easy and tries to work around your treatment. It knows your treatment will come with certain consequences and it will try to exploit this situation by keeping you guessing between cancer activity and these consequences. It really hates observant medical staff and patients, particularly those who understand Neuroendocrine Cancer.

Unfortunately for Neuroendocrine Cancer, there is now more knowledge about its devious activities and the latest statistics indicate it’s starting to be caught earlier. Nonetheless, we cannot afford to become complacent.

Neuroendocrine Cancer hates awareness and it will be extremely happy if you don’t share this post.

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 – don’t break my heart!

dont break my heart

NEW – 2017 guidance issued.  Diagnosing and Managing Hedinger Syndrome (Carcinoid Heart Disease) in Patients With Neuroendocrine Tumors – An Expert Statement published in the Journal of the American College of Cardiology.

The following are key points to remember from this Expert Statement about the diagnosis and management of carcinoid heart disease in patients with neuroendocrine tumors:

  1. Carcinoid heart disease is a frequent occurrence in patients with carcinoid syndrome and is accountable for substantial morbidity and mortality.
  2. The pathophysiology of carcinoid heart disease is not well understood; however, chronic exposure to excessive circulating serotonin is considered one of the most important contributing factors.
  3. N-terminal pro–B-type natriuretic peptide (NT-proBNP) appears to be the best biomarker to date for screening carcinoid syndrome patients for evidence of clinically significant carcinoid heart disease (Evidence Level 2-3, Grade B).
  4. Measurement of either 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA) or plasma 5-HIAA is mandatory for diagnosis and follow-up of carcinoid syndrome. Furthermore, a 24-hour urinary 5-HIAA level >300 μmol/24 hour is a useful marker for identifying those at risk of developing carcinoid heart disease (Evidence Level 2, Grade B).
  5. Transthoracic echocardiography remains the gold standard for diagnosis and follow-up of carcinoid heart disease. It should be performed in all patients with carcinoid syndrome and high suspicion of carcinoid heart disease, such as clinical features or raised NT-proBNP and/or 5-HIAA levels. For established carcinoid heart disease, echocardiography should be performed if dictated by a change in clinical status; otherwise/thereafter every 3-6 months, depending on the severity of established carcinoid heart disease and clinical status (Evidence Level 2, Grade B).
  6. Cardiac magnetic resonance can be used to evaluate the pulmonary valve, identify cardiac metastases, and assess right ventricular size and function (Evidence Level 2, Grade B).
  7. Long-acting formulations of somatostatin analogs are the standard treatment used to alleviate symptoms related to the carcinoid syndrome, and prevent the development and/or progression of carcinoid heart disease (Evidence Level 2, Grade B).
  8. In cases of carcinoid syndrome that are refractory to somatostatin analogs, options include escalation of the somatostatin analog dose to above labeled doses, addition of IFN-alfa, or peptide receptor radionuclide therapy (PRRT). The oral serotonin synthesis inhibitor, telotristat, represents a promising agent to improve symptoms of the carcinoid syndrome; however, it is not yet approved, and is currently only available for compassionate use in the United States. Given the limited data, everolimus cannot currently be recommended for the treatment of carcinoid syndrome (Evidence Level 2-4, Grade B/C). (NOTE: Since publication, PRRT now widely approved).
  9. The patient with carcinoid heart disease should be managed by a specialized multidisciplinary team, within a setting of a specialized neuroendocrine tumor (NET) center (Evidence Level 5, Grade D).
  10. An experienced medical (cardiologists and NET specialists with involvement of other specialists as necessary), surgical, and anesthetic team approach to the patient with carcinoid heart disease is critical to provide state-of-the-art management for these patients (Evidence Level 5, Grade D).
  11. The choice of valve prosthesis should be individually tailored on the basis of the patient’s bleeding risk, and possible future therapeutic interventions. Biological valve prostheses are the preferred option (Evidence Level 4, Grade D).
  12. To prevent a carcinoid crisis during surgery, the patient should be started on an IV octreotide infusion at a rate of 50-100 mcg/h at least 12 hours preoperatively; this should be continued throughout the procedure and until stable. Patients should be monitored for occurrence of bradycardia if high doses of octreotide are used (Evidence Level 4, Grade C).
  13. Patients with confirmed carcinoid heart disease should be referred to a NET center with cardiology and cardiac surgery departments having expertise in dealing with this complex pathology (Evidence Level 5, Grade D).

chd treatment

A useful abstract of Carcinoid Heart Disease information written by a patient for patients is below.

Neuroendocrine Cancer has certain unique features whereby tumours can produce one or more symptoms which are known collectively as a syndrome.  Neuroendocrine Tumours secreting excess amounts of serotonin, can be accompanied by Carcinoid Syndrome which if not diagnosed and treated early enough, can lead to an additional complication known as Carcinoid Heart Disease (CHD) or Hedlinger Syndrome. However, very late diagnoses can present with CHD already in place.

Excess serotonin, a hormone released by NETs into the bloodstream seems to be the prime and lead suspect for causing thick ‘plaques’ or fibrosis tissue within the heart muscle and damage to (mainly) the tricuspid and pulmonary valves on the right side of the heart which can become ‘tightly narrowed’ or ‘leaky’.  Other substances associated with Carcinoid Syndrome may also be involved (e.g. tackykinins). The presence of liver metastases may allow large quantities of these substances to reach the right side of the heart without being filtered out by the liver but the primary and other secondaries can still contribute to the problem. It’s important to note that the damage is nearly always caused by excess secretions of substances from malignant neuroendocrine cells rather than any direct metastatic involvement of the heart.

Patients with carcinoid heart disease normally present with symptoms such as breathlessness (dyspnea), fatigue, ascites, swollen ankles (edema). However some patients can be asymptomatic.  The left side of the heart is relatively protected, with the pulmonary circulation filtering out the majority of the serotonin and other substances produced by the tumours.  However, involvement of the left-sided valves can sometimes be seen in patients with very active metastatic disease, bronchial carcinoid or those with an existing heart condition known as Patent Foramen Ovale (hole in the heart).

When I was diagnosed in 2010, I was displaying symptoms of carcinoid syndrome and had to undergo a plethora of tests including something called an Echocardiogram – a sonogram (ultrasound) of the heart. Note – it is NOT abbreviated as ECG, which lay persons often use as an abbreviation for an Electrocardiogram – a totally different test.  Carcinoid heart disease is a relatively late manifestation of neuroendocrine tumours; however, it can have an impact on the prognosis of these patients. Thus, early testing is vital for each patient presenting with carcinoid syndrome so that treatment can be considered. Whilst there are certain biomarkers which might indicate the potential for Carcinoid Heart Disease to be present, Echocardiography is the gold standard for detection. Depending on the results of the Echocardiogram, two further investigatory tests may be ordered up – transoesophageal echocardiogram and cardiac catheterisation.  Patients without symptoms can undertake a blood test called NT-proBNP which can function as a screening test.

If you ‘google’ Carcinoid Heart Disease, be careful where you look as there are some statistics to be found in terms of incidence and prognosis.  I suspect they may be out of date and have yet to catch up with improvements in the latest diagnostic and treatment techniques. Either that or they fail to mention the disease might only be clinically significant in much smaller percentages.

On a positive note, I sense major strides in worldwide awareness campaigns which should lead to earlier diagnosis and therefore earlier treatment for Neuroendocrine Cancer. Combine that with new and innovative treatments in debulking/removing/shrinking tumours and controlling syndromes – particularly the use of somatostatin analogues with the latter, should mean that fewer people will succumb to this additional complication. I don’t see a lot of Carcinoid Heart Disease posts on the various forums which hopefully is a good sign.

I did blog about a new treatment for Carcinoid Syndrome called  XERMELO (Telotristat Ethyl) read here.  At ENETS 2016, a report claimed that it appeared to ‘halt Carcinoid Heart Disease’ or certainly reduce the risk.  Reducing the risk sounds feasible as Telotristat Ethyl reduces the ability to manufacture serotonin to levels which appear subthreshold to that which stimulates fibrosis associated with CHD. This drug might prevent the need for valve surgery in many cases, and enable the use of bioprosthetic valves in others, without recurrent fibrosis.  You can read the ENETS poster here.

Although I’m fairly stable, I still try to get an Echocardiogram on an annual basis and am very happy to have this one in my ‘test golfbag’. The procedure is painless and takes around 20-30 minutes.  My results have always been OK.  Information on the guidelines for CHD have been a bit sparse but a new paper published has proposed an ‘Algorithm for the Screening and Investigation of CHD.

Proposed Algorithm for the Screening and Investigation of CHD This graphic provides an algorithm for how patients with metastatic (serotonin-producing) neuroendocrine tumors (NETs) should be screened and assessed for carcinoid heart disease (CHD), including, importantly, when to refer to cardiology. f/u = follow-up; NT-proBNP = N-terminal pro–B-type natriuretic peptide.

If you have time please check out this excellent video presentation on Carcinoid and Your Heart with cardiologist Dr. Jerome Zacks from Mount Sinai Hospital and the Carcinoid Heart Center, both in New York City.

Please also note that fibrosis due to excess serotonin (and other substances) can also induce fibrosis in the mesentery, retroperitoneum, pleural and pulmonary cavity and the skin. This is fully covered in my article Neuroendocrine Cancer: Fibrosis – an unsolved mystery?

Carcinoid vs Neuroendocrine

OPINION

CARCINOID misnomer etc

There’s a constant debate regarding the validity of the term ‘Carcinoid‘.  I’ve posted about this a few times and as far as I know, the debate has been raging for some years.

You may have noticed that ‘Carcinoid’ is often used as a standalone word and tends not to be suffixed with the word ‘Cancer’ or ‘Tumour’ – unlike Bowel Cancer, Breast Cancer, Prostrate Cancer, Lung Cancer, Brain Tumour, etc.  Nobody goes around saying “Breast” or “Bowel” do they?  But they happily say “Carcinoid”.  Unfortunately, the term ‘Carcinoid’ has become entrenched in both pathology and clinical literature over the past 100 years. The main problem with the word Carcinoid is that it means different things to different people. Some use the term almost exclusively to designate serotonin-producing tumours that arise from the enterochromaffin cells that can result in carcinoid syndrome i.e. most commonly in the appendix, small intestine, stomach, lung, rectum and uncommonly in other places. Some use it to (incorrectly) refer to all Neuroendocrine Tumours. The most worrying connotation of the use of the word ‘Carcinoid’ is the belief that they all have benign clinical and biological behaviour.  That is dangerous thinking and has the potential to kill people.  Fortunately, NET specialists are starting to move away from using the word – check out the quote below:
carcinoid falling out of favor

Siegfried Oberndorfer
Siegfried Oberndorfer

The Origins

The following history of ‘Carcinoid’ is well documented: Siegfried Oberndorfer (1876-1944) became the first to adequately characterise the nature of Carcinoid tumours and refer to them as “benign carcinomas.” During his tenure at the Pathological Institute of the University of Munich, Oberndorfer noted in 1907 that the lesions were distinct clinical entities and named them “karzinoide” (“carcinoma-like“), emphasizing in particular their benign features. However, In 1929 he amended his classification to include the possibility that these small tumours could be malignant and also metastasise. (Author’s note – a name change would have been handy at this point).

100 years later

NANETS, UKINETS and ENETS seem to defer to the WHO classification nomenclature and it is here another term is introduced – Neuroendocrine Neoplasms (NENs).  NANETs state that “all of the entities under discussion are neoplastic, and neoplasm is therefore a more accurate term than tumor, which means only a mass“.  These organisations tend to use the term Neoplasm as a catch-all for all Neuroendocrine disease and then the term ‘tumor’ and ‘carcinoma’ applies to well and poorly differentiated respectively.  It’s worth noting that since 2010, the WHO classification is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential. Neuroendocrine Carcinoma is malignant by defintion. All of this has been reinforced in the 2017 publication. The term ‘Carcinoid’ is conspicuously missing from these texts.

To put it simply – the term ‘carcinoid’ is no longer credible

Due to its historical meaning, Carcinoid does not adequately convey the potential for malignant behaviour that accompanies many of these neoplasms as described above.  The term Carcinoid decodes to ‘Carcinoma like’.  Contextually “Carcinoid Cancer” decodes to “carcinoma like cancer” which is, of course, totally misleading and its use simply perpetuates the claim by some that it is ‘not a proper cancer’.  If we only needed one reason to ditch the word ‘Carcinoid’, this would be it.

carcinoid is inadequate oberg quote 2016

I mentioned confusion above and this has led to a hybrid effect of naming the condition.  For example, there is a tendency by some (including medical establishments and patient organisations) to use the term ‘Carcinoid’ and ‘Neuroendocrine Tumors’ interchangeably which is patently incorrect. Neither is it helpful that many patients and organisations continue to refer to this disease as “Carcinoid Neuroendocrine Tumor”, “Neuroendocrine Carcinoid Tumor”, “Neuroendocrine Carcinoid Cancer”, “Carcinoid/Neuroendocrine”, “CNET”; and many other variations along these lines. Many seemingly credible organisations will say “Carcinoid and Neuroendocrine Tumors” not realising it’s a contradiction in terms. Continued use of the term in any phrase or standalone context is not doing our case for recognition any good – it’s bad enough that some seem to cling to outdated and invalid diagnostic clichés and icons from the 1980s.  All of it needs to go.

carcinoid npf quote

I know I’m not alone in this thinking given the decrease of its use in the NET world, including NET Specialists (see lead graphic) and NET Specialist organisations (some have changed their names).  There’s an interesting article written by a NET specialist where the term ‘carcinoid’ is described as “unfortunate”, “misleading”, “outmoded”, “archaic”, “confusing” and “misnomer”. Exactly!  In the recent SEER NET study, a NET specialist reaffirmed this thinking by stating that “the belief these tumors did not metastasize, did not reach any great size, and appeared harmless, has since been proven false”.  Continued use of the term ‘Carcinoid’ has the potential to regress this thinking.  We must not let this happen.

referring to carcinoid

So what terms should we be using?

People and organisations will be out of date with modern Neuroendocrine Neoplasms nomenclature and some will still want to continue with their own nomenclature (….. and because of the confusion, some will fall into both categories not realising they’re out of date).  Here’s a classic example of the problem we face – the American Cancer Society(ACS) does not even list Neuroendocrine Tumor as a cancer type.  Instead you can find “Gastrointestinal Carcinoid Tumors” and “Lung Carcinoid Tumor”. You’ll find Pancreatic NETs inside Pancreatic Cancer.  Americans should harangue the ACS to get this right. I could go on with many similar observations on seemingly respectable sites. I intentionally used a US example as this country appears to be way behind in the changes to NET nomenclature, pretty surprising as they tend to be at the forefront of many other aspects in the world of NETs.

Personally, I think the acceptance of a common worldwide nomenclature should come from the World Health Organisation (WHO) classification for Neuroendocrine Neoplasms.  They are divided into a number of chapters including ‘Endocrine Organs’, Digestive System, Lung Tumours….. and no doubt some others.  Frustrating, but medical people tend to look at things in anatomical terms. Nonetheless, the agreed classification nomenclature for the whole group of Neuroendocrine Neoplasms can be found with some research and access to clinical publications.  The correct nomenclature should then be flowed down in regional groupings, e.g. ENETS representing Europe, NANETS representing North America, etc.  As I understand it, ENETS and UKINETS are already essentially aligned with WHO and NANETS appears to be. From these organisations, the use of the correct terminology should then rub off on patients, patient advocate organisations and general cancer sites.  However, the biggest challenge will be with hospitals/medical centres, cancer registries and insurance companies whose medical record processing is run using reference data (think drop down selections and database structures).  Easier said than done but ‘change’ always has to start somewhere.  Technically it has started (albeit late) as the big NET medical organisations are already starting to reduce the use of outmoded words such as ‘carcinoid’.

I once argued that the term ‘carcinoid’ needed to be retained as it represented a histopathological grouping of a particular type of NET comprising mostly appendiceal, stomach (gastric), rectal, small intestine and lung NETs.  However, reading through the ENETS 2016 guidance in conjunction with the most up to date WHO classification publications, I’ve changed my mind after noticing they no longer use the word ‘Carcinoid’ in relation to a tumor type.  Rather, they use the latest WHO terms above and then use the anatomy to distinguish the different types of NET (like we already do for Pancreatic NET or pNET).

Perhaps patients can lead the way here ………

Rather than say:

‘Carcinoid’ or ‘Carcinoid Tumor’….. why not say Neuroendocrine Tumor or NET (adding your primary location if required – see below);

‘Carcinoid Cancer; ….. why not say Neuroendocrine Cancer;

‘Lung Carcinoid’ ….. why not say Lung NET (adding typical or atypical if required);

‘Small intestine Carcinoid’, why not say Small Intestine NET (or ‘SiNET which is becoming popular); p.s. I’m not a fan of ‘small bowel’ due to the potential for confusion with the widely used term ‘bowel cancer’);

‘Gastric Carcinoid’, why not say Gastric NET (adding your type if required);

‘Rectal Carcinoid’, why not say Rectal NET;

‘Appendiceal Carcinoid’, why not say Appendiceal NET;

…. and so on.  And you can add your stage and grade/differentiation for a richer picture.

You can listen to a very well known NET Specialist say something similar in this video here.

Worth noting that even ENETS and NANETS cannot agree on tumor type terminology – the latter uses Small Bowel NETs (SBNETs) whereas ENETS uses Small Intestine NENs (SiNENs). I did say it’s easier said than done.

As I said above, the term ‘Carcinoid’ has become entrenched in both pathology and clinical literature over the past 100 years so it will still appear in many texts and need to be searchable online to support medical and advocacy business.  However, these are technical issues and I don’t therefore believe people need to use the terms to make them searchable online.  I tag all my posts with ‘Carcinoid’ even if I don’t mention the word in my text.  I have started only using the term for context when it is required and am currently reviewing all of my posts to ensure that is still the case.

Hang on…what about Carcinoid Syndrome

When someone wants to know which syndrome you have, you can’t just state (say) “small intestine syndrome” or “midgut syndrome”.  ‘NET Syndrome’ doesn’t work either as there are several NET syndromes.  This has led to the situation where people try to drop the word ‘carcinoid’ and just say “the syndrome” which is even more confusing! I accept this one is a difficult challenge but I don’t believe it’s insurmountable, just needs some willpower and agreement.

What about Carcinoid Heart Disease

Personally I don’t see why this cannot be renamed to ‘Neuroendocrine Heart Disease’ or its technical name – ‘Hedinger syndrome’.

What about Carcinoid Crisis

World renowned NET specialists already make statements that these issues can apply to all types of NET; and it’s well-known that a similar crisis situation already applies to other types e.g. Pheochromocytomas.  I cannot see why something along the lines of ‘Neuroendocrine Crisis’ or ‘NET Crisis’ would not be acceptable.

Summary

We as patients are unlikely to be able to force changes on the medical and insurance communities but we can be a ‘force for change’ by setting the example of using a correct and more apt terminology to describe our disease.

 

Thanks for listening

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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