NET Syndromes – chicken or egg?


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

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

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

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

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

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

Thanks for listening

Ronny

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Neuroendocrine Cancer – tumour markers and hormone levels


 

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. Technically, a biopsy is a tumour marker but I’ll not be discussing that today. I more or less covered biopsies in my blog on NETs – Stages and Grades.

I’d also like to talk about certain other 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.  The post will not cover routine blood tests (i.e. complete blood count etc) as although they may point to a problem, these tests do not necessarily indicate a particular type of NET.

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.

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 between in-country labs through the use of different commercially available ‘testing kits’. Moreover, the ‘normal’ test range can vary from hospital to hospital, even within the same tests. I can only imagine that 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.

Here’s two tips I always give people:  1 – always get your results (preferably on paper) and track them yourself (I use a spreadsheet).  2 – When comparing results inside patient forums, always add 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!

NET 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.

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.

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 (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.

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 ATCH (also called ectopic ATCH). 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!

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!

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).

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, in the bronchus or ovary you 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.

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 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 nonfunctional:

  • 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.
  • 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.

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 simultanously 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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