Genetics and Neuroendocrine Tumors


In my article ‘Ever wonder what caused your NET’, I concluded that currently, the only known scientifically explained causes for NETs were hereditary/genetic in nature.  This is mostly associated with those who have MEN syndromes (yes, they are a syndrome not a type of tumour) and a few other less common types of NET including Pheochomocytoma/Paraganglioma (Pheo/Para) and Medullary Thyroid Carcinoma (MTC) (the familial version of MTC is often referred to as FMTC). However, please note this does not mean that all those diagnosed with pancreatic, parathyroid, pituarity, Pheo/Para and MTC tumours, will have any hereditary or genetic conditions, many will simply be sporadic tumors.

In recent years, it has become increasingly apparent that a number of Neuroendocrine tumours arise as a result of germline genetic mutations and are inherited in an autosomal dominant pattern. The number of genes implicated is increasing.

Apparently, 5-10% of Gastroenteropancreatic NETs (GEP NETs) are estimated to have a hereditary background. Hereditary syndromes associated with these include Multiple Endocrine Neoplasia (MEN), Von Hippel Lindau (VHL), Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis (TS) and others. People who have a genetic condition may present with the tumors (perhaps along with an associated functional hormone syndrome) and so the genetic condition if there is one, may not be known at this point.

genetics locations
Overview of genes with recurrent mutations in NETs and their distribution accordingly to anatomical location. Please note the percentages on the above diagram may differ depending on where you look).  
Citation: European Journal of Endocrinology 174, 6; 10.1530/EJE-15-0972

How will I know if I am affected? 

Some people do worry about this, often because of what they find on the internet including inside patient forums.  I suspect some people already know via family connections and as an example (there are many), I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise a suspicion for MEN1 and be investigated.

Many people say how do I know, how do I check and this is obviously a delicate subject.  Of course, your first port of call should be your NET specialist if you suspect or know of any connection.

Thus why I was interested in a paper published in Springer Link – titled “When should genetic testing be performed in patients with neuroendocrine tumours.”  When reading, you’ll find it’s actually much more than that! Check it out here:

Crossref DOI link: https://doi.org/10.1007/s11154-017-9430-3

In this review, the authors examined the features which may lead a clinician to suspect that a patient may have an inherited cause of a NET and they outlined which underlying conditions should be suspected. They also discussed what type of screening may be appropriate in a variety of situations. If there is a way to identify which patients are likely to have a germline mutation, this would enable clinicians to counsel patients adequately about their future disease risk, and allows for earlier detection of at-risk patients through family screening. There’s a couple of minor errors in the text but I’ve contacted the authors who also agreed they should have included the pituitary.

The authors focused on presentations of NETs of the gastrointestinal system, chromaffin cell tumours (Pheochromocytoma and Paraganglioma) and Medullary Thyroid Carcinoma. Pituitary tumors (normally associated with MEN1), were not considered in scope for the review.  Interesting thought, the review includes news of a move by endocrinologists to reclassify ‘Pituitary Adenomas’ as Pituitary NETs (PitNETs). Read the abstract here.  This would appear to be in line with a gradual shift from the benign nomenclature associated with certain NETs to the ‘malignant’ potential of these type of tumors.  The abbreviation is also in line with others, e.g. pNET, SiNET, etc.  A useful reminder that we must stop using the term ‘Carcinoid‘ as this is regressing this extremely useful initiative to highlight the malignant potential of all NETs.

There also appears to be some linkage to the study looking at the possibility of familial Small Intestine NETs (SiNETs).  You can read more about a US registered trial here (with apologies for use of the now defunct term ‘Carcinoid‘).

This is a complex subject and the text above is very basic. If you wish to dig further, the quoted reference is a good read.  Just to emphasise, it’s aim is to provide advice about when to recommend genetic testing for NETs, and in doing so provides some useful reference information.  Please also note they are finding new genetic links all the time so there could be some omissions of recently discovered genes but the article remains good enough as a primer on the subject.  It’s broken down into 4 distinct tumor groupings:

1.  Gastroenteropancreatic (GEP NETs)

2.  Bronchial/Thymic NETs

3.  Pheochromocytoma/Paraganglioma  The familial connection with Pheo/Para is complex. Up to 13 genes have been identified including NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2(SDH5), TMEM127, MAXm EPAS1, FH, MDH2.  Read more here (recent update)The NIH also have a useful section – click here.

4.  Medullary Thyroid Carcinoma

You may also find this article from the National Cancer Institute very useful.  It has a wider scope but a different aim. Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version”

I also noted the UKINETS Guidelines for NETs has a section on genetics and includes something called Carney Complex.

Thanks for reading

Ronny

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Neuroendocrine Cancer – tumour markers and hormone levels


blood tests

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.  Opinions differ but many texts I found did suggest stopping PPIs for 2 weeks before the CgA blood test.  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 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 (although I’ve seen some labs increase that to 10 or 12). 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. Taking 5HTP supplements are possibly not advised either prior to the test either.

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

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

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

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

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

Gastric NETs (Stomach)

Testing will be different depending on the Type:

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

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

NETs of the Pancreas (pNETs)

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

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

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

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

Notes:

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

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

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

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

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

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

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

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

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

Insulinoma – Insulin, Proinsulin, C-peptide

Gastrinoma– Gastrin, Gastrin pH

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

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

Somatostatinoma – Somatostatin (plasma somatostatin like immunoreactivity)

PPoma – Pancreatic Polypeptide (PP)

Other NETs/Syndromes

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

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

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

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

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

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

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

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

Cortisol

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

Other hormones related to ACC include:

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

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

Aldosterone – weight gain, high blood pressure.

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

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

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

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

The Future – Molecular Markers?

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

Tumour Markers and Hormone levels – complex subject!

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Neuroendocrine Cancer: Troublesome Thyroids


thyroid

In 2013, just when I thought everything seemed to be under control, I was told I had a ‘lesion’ on the left upper lobe of my thyroid.  At the time, it was a bit of a shock as I had already been subjected to some radical surgery and wondered if this was just part of the relentless march of metastatic NET disease.  The thyroid gland does in fact get mentioned frequently in NET patient discussions but many of the conversations I monitored didn’t seem to fit my scenario – cue relentless study! I’ve been meaning to write this blog for some time but here is a synopsis of my research translated into ‘patient speak’.  This is intentionally brief, it’s a big subject.  I’ll finish off with an update on where I am with my thyroid issue.

Where is the thyroid and what does it do?

Before I found out about my thyroid problem, I had absolutely no idea what its function was.  I can tell you know, it’s a small organ but it has a massive job! 

It lies in the front of your neck in a position just below your ‘Adam’s apple’. It is made up of two lobes – the right lobe and the left lobe, each about the size of a plum cut in half – and these two lobes are joined by a small bridge of thyroid tissue called the isthmus. It is sometimes described as butterfly shape.  The two lobes lie on either side of your wind-pipe. The fact that it comes up a lot in NET patient discussions is hardly surprising as it’s an endocrine organ responsible for making two hormones that are secreted into the blood: Thyroxine (T4) and Triiodothyronine (T3). These hormones are necessary for all the cells in your body to work normally.

Do I have Thyroid Cancer?

I’ve had a number of biopsies on the thyroid lesion, several fine needle aspiration (FNA) and one ‘core’.  The FNAs were generally inconclusive and the core confirmed fibrous tissue only.  However, the general diagnosis is inconclusive and I have been labelled “THY3F”. Curiously this decodes to “an abnormality is present but it could either be a benign (non cancerous) growth or a malignant cancerous growth of the follicular cells.     A quick primer on Thyroid Cancer is below if you’re interested.

HOWEVER ………

It’s easy to worry about irregularities showing up on scans if you have NETs. Take the thyroid for example, the Ga68 PET has a habit of ‘lighting up’ thyroids – this is a worry because it’s an endocrine organ; and there is a type of thyroid NET (not forgetting the parathyroid), and NETs have a habit of metastasizing to strange places. Sure, you should get it checked out when this happens, but while you will only hear about the outliers on social media, statistically, the vast majority of thyroid nodules are benign. We know about ours because we get so many scans but many people will probably never know and will probably never be bothered by them either. When you look at the figures below, it becomes clear that many NET patients are going to have a thyroid nodule regardless of their diagnosis.

The following is a list of facts regarding thyroid nodules:

  •  Thyroid nodules are three times more common in women than in men
  •  30% of 30-year-old women will have a thyroid nodule.
  •  One in 40 young men has a thyroid nodule.
  •  More than 95% of all thyroid nodules are benign (non-cancerous growths).
  • Some thyroid nodules are actually cysts, which are filled with fluid rather than thyroid tissue.
  • Purely cystic thyroid nodules (thyroid cysts) are almost always benign.
  • Most women will develop a thyroid nodule by the time they are 50 years old.
  • The incidence of thyroid nodules increases with age.
  •  50% of 50-year-old women will have at least one thyroid nodule.
  •  60% of 60-year-old women will have at least one thyroid nodule.
  • 70% of 70-year-old women will have at least one thyroid nodule.

Fear of spread

It’s easy to be concerned about irregularities showing up on scans if you have NETs. However, the Ga68 PET has a habit of ‘lighting up’ thyroids and this is a double worry because it’s an endocrine organ, and there is a type of thyroid NET (not forgetting the parathyroid). But it eventually became clear through research that most are unconnected. Sure, you should get it checked out, but while you will only hear about the outliers on social media, the vast majority of cases are benign.  If you constantly fear cancer spread with every single issue you undergo as a human being, you probably need some help.  You may therefore find my ‘fear’ articles a useful read plus there are two videos presented by professionals who help caner patients cope with these issues:

Article 1: Warrior or Worrier?

Artilce 2:  8 tips for conquering fear.

Thyroid overdiagnosis and overtreatment. You can find many medical papers confirming that incidence of thyroid tumour diagnosis has increased dramatically in many countries in the developed world over the past three decades. Papillary thyroid cancer, which has been responsible for virtually the entire increase, is rarely lethal. The 20 year survival rate is greater than 90%, and approaches 100% for the smallest cancers. The increasing incidence is most likely due to overdiagnosis—the detection of subclinical cancers never destined to cause harm. This conclusion has been reached because the incidence has been primarily due to the detection of small papillary cancers, mortality due to thyroid cancer has not changed significantly, and small foci of papillary thyroid cancer are commonly found at autopsy in people who died of other causes. Overdiagnosis is a problem because it exposes people to the potential side effects of treatment, but without an equal expectation of benefit, because the cancer is unlikely to advance. We know about ours because we get so many scans.

Issues above the diaphragm

There can be other issues with Thyroids including cancer and clearly this was my concern when the word ‘lesion’ was mentioned.  At this point, it’s worth mentioning something from my cancer history which I initially assumed was related but it would appear to be a coincidence (for the time being …..).  When I say “above the diagphragm”, I mean above the abdoment in the general neck and chest area. I also have a hotspot in my left supraclavicularfossa (SCF) lymph nodes (near the clavicle), geographically close to the thyroid (and my lesion is left-sided).  5 nodes were removed from this area in Feb 2012 for an exploratory biopsy which subsequently tested negative and CT and Ultrasound both show nothing vascular or pathologically enlarged. BUT …. there is still a hotspot showing on a subsequent Octreoscan and Ga68 PET since the nodes were removed in 2012.   For the record, I also had positively tested nodes removed from my left axillary (armpit) during the same procedure (my distant disease has always been left-sided).

The surgeon who operated on my left axillary and SCF nodes also specialises in Thyroids and so it was an easy decision to ask to be referred to him. He explained that whilst he could just take the left lobe or the whole thyroid, it would mean lifelong treatment to add to my current burden and perhaps for something which will never trouble me. As nothing is palpable and I have no symptoms, I agreed to a ‘watch and wait’ approach. I now have regular tests and I saw him Endocrine MDT annually for a blood test review and ultrasound check (but see update below).

See EndocrineWeb for more detail about thyroid issues unrelated to NET.

Latest update as at 15 Jan 2019

After monitoring for the first two years, my specialist was not happy with TSH/T4 blood results (elevated for the second time and also on a retest). On 20 March 2018, following an Endocrine appointment, I was put on a trial dose of 50mcg of Levothyroxine to counter the thyroid panel results indicating mild hypothyroidism. Levothyroxine is a thyroid hormone replacement.  My subsequent two x thyroid panel results are back in the middle of the range so all is good.   Am detecting a slight increase in available energy.

The results of my first Ga68 PET scan in June 2018 indicated some “uptake” but the report inferred it was physiological uptake (false positive).  In fact, at my 2019 appointment, the thyroid lesion is slightly smaller on the latest ultrasound. I’m personally fairly certain this is not connected to NETs and my Endocrine MDT have now referred me back to be survellanced by the NET MDT, they remain on call for any issues.

What else can go wrong with a thyroid?  

Apart from cancer, the main issues appear to be an underactive Thyroid or an overactive Thyroid – known respectively as Hypothyroidism (not enough thyroxine is produced for the body’s needs) and Hyperthyroidism (too much thyroxine is produced for the body’s needs). Of course, these issues can be caused or made worse by cancer.

Hypothyroidism – If too little of the thyroid hormones are produced, the cells and organs of your body slow down. If you become hypothyroid, your heart rate, for example, may be slower than normal and your intestines work sluggishly, so you become constipated.  Key symptoms: tiredness, feeling cold, weight gain, poor concentration, depression. Some of these symptoms look familiar?  The word ‘hashimoto’s’ also comes up on patient forums frequently – this is related to hypothyroidism (underactive).

Hyperthyroidism – If too much of the thyroid hormones are secreted, the body cells work faster than normal, and you have Hyperthyroidism. If you become hyperthyroid because of too much secretion of the hormones from the thyroid gland, the increased activity of your body cells or body organs may lead, for example, to a quickening of your heart rate or increased activity of your intestine so that you have frequent bowel motions or even diarrhoea.  Key symptoms – weight loss, heat intolerance, anxiety, and, sometimes, sore and gritty eyes.  Hmm, again, some of these look familiar?

Check out this excellent short video fromWebMD – click here.  It’s based on USA but most of it is relevant globally.

It’s also worth noting thatsomatostatin analoguesmight cause a “slight decrease in Thyroid function” (it actually states words to this effect in the Lanreotide and Octreotide patient leaflets).  Thus why I advise you not to be underactive with your Thyroid surveillance – read more click here

Routine ‘Thyroid blood tests’ from your doctor will confirm whether or not you have a thyroid disorder.  I now test for TSH (thyroid-stimulating hormone), T3 and T4 every 6 months. My levels are back to normal ranges since being prescribed thyroid hormone replacement therapy.

Remember:  Hypo is ‘underactive’, Hyper is ‘overactive’.  Sometimes there are very few symptoms.

Also worth mentioning something called the ‘Parathyroid’ as these glands can frequently be related to NET Cancer (see my blog on Multiple Endocrine Neoplasia (MEN)). It’s another subject in its own right but I just wanted to emphasise that this is a totally different organ with a totally different function (it regulates Calcium).  They are located adjacent to the Thyroid, thus the term ‘para’.

Quick primer on Thyroid Cancer

 There are a number of different types of Thyroid Cancer

Papillary thyroid cancer is the most common type of thyroid cancer, accounting for about 80% of thyroid cancers. While papillary thyroid cancer typically occurs in only one lobe of the thyroid gland, it may arise in both lobes in up to 10% to 20% of cases. Papillary thyroid cancer is most common in women of childbearing age. It sometimes is caused by exposure to radiation. Even though papillary thyroid cancer is usually not an aggressive type of cancer, it often metastasizes (spreads) to the lymph nodes in the neck. Papillary thyroid cancer treatment usually is successful.

Follicular thyroid cancer accounts for about 10% of thyroid cancers. Like papillary thyroid cancer, follicular thyroid cancer usually grows slowly. Its outlook is similar to papillary cancer, and its treatment is the same. Follicular thyroid cancer usually stays in the thyroid gland but sometimes spreads to other parts of the body, such as the lungs or bone. However, it usually does not spread to lymph nodes. It is more common in countries where diets do not contain enough iodine.

There is a type of thyroid tumour which has recently been removed as a type of cancer.  “Encapsulated follicular variant of papillary thyroid carcinoma” is now known as “noninvasive follicular thyroid neoplasm with papillary thyroid-like nuclear features” or NIFTP.  The word ‘carcinoma’ has gone.  Read about this here.

Hurthle cell carcinoma, also called oxyphil cell carcinoma, is a type of follicular thyroid cancer. Most patients diagnosed with Hurthle cell cancer do well, but the outlook may change based on the extent of disease at the time of diagnosis.

Medullary thyroid cancer (MTC) is the only type of thyroid cancer that develops in the parafollicular cells of the thyroid gland. It accounts for 3% to 10% of thyroid cancers. Medullary cancer cells usually make and release into the blood proteins called calcitonin and/or carcinoembryonic antigen, which can be measured and used to follow the response to treatment for the disease. Sometimes medullary cancer spreads to the lymph nodes, lungs or liver before a nodule is found or the patient has symptoms. MTC can be treated more successfully if it is diagnosed before it has spread. There are two types of MTC:

  • Sporadic MTC is more common, accounting for 85% of medullary thyroid cancers. It is found mostly in older adults and is not inherited.
  • Familial MTC is inherited, and it often develops in childhood or early adulthood. If familial MTC occurs with tumours of certain other endocrine organs (parathyroid and adrenal glands), it is called multiple endocrine neoplasia type 2 (see my blog on MEN 2).

Anaplastic thyroid cancer is the most dangerous form of thyroid cancer. It is makes up only 1% of thyroid cancers. It is believed that anaplastic thyroid cancer grows from a papillary or follicular tumour that mutates further to this aggressive form. Anaplastic thyroid cancer spreads rapidly into areas such as the trachea, often causing breathing difficulties.  Anaplastic thyroid cancer sometimes is called undifferentiated thyroid cancer because the cells are so different from normal thyroid tissue.

Thyroid cancer is not very common but diagnoses are ‘skyrocketing’ most likely due to advanced detection techniques.  Most are very slow-growing with 5 year survival of 97% according to MD Anderson. There is a very interesting article about the overdiagnosis of Thyroid cancer which I found useful given my situation. You can read it here.

Thyroid ‘nodules’ would appear to be very common with 50-70% of all 50-70 year olds having at least one nodule present and statistically, 95% of these are benign (see EndocrineWeb)

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Neuroendocrine Cancer – it can be ‘smoke and mirrors’

Neuroendocrine Cancer smoke and mirrorsIn a previous life, I used the term ‘smoke and mirrors’ quite a bit.  I was used to dealing with many different types of people, some who wanted something, some who wanted to buy or sell something. Most of the time it was overt but the devil was usually in the detail.  Sometimes there was an element of ‘covertness’ or a ‘hidden agenda’.  It was always tricky working out the details of the hidden agenda and sometimes it was only known when it was too late.  Some of you will already be seeing where I’m going with this line of thinking – if so, you worked out my hidden agenda!

‘Smoke and Mirrors’ is basically a term connected to the art of deception, a con trick, a way in through confusion and trickery (think magicians on TV!). 

Whilst certain cancers can appear with precise symptoms and leave you under no illusion what you’re facing, others can be a bit more circumspect – Neuroendocrine Cancer can be one of those.  It will fool you into thinking you’re not even ill and even when it puts its head above the parapet, this can come over as a routine illness and/or vague symptoms which will deceive both you and your physicians.   Thus why awareness is really important.  I won’t repeat my key messages but you can find them here in my blog entitled “Neuroendocrine Cancer can be silent – but it doesn’t mean we should be” – the more these posts and ones like it are shared, the quicker we can discover the hidden agenda. 

I have another hidden agenda!  I was inspired to write this post by my friend and blogger Shannon – she writes a blog called ‘A tale of two tumours’.  I really like this blog because there are no hidden agendas, what you see is what you get and she has catchy titles.  I also like Shannon because she has a great attitude despite the fact that she is probably still looking for the ‘hidden agenda’ or at least bits of it (then again perhaps we all are?).

Shannon has one of the uncommon variants of our disease, one of those tricky cases it would seem.  Her issues started some time ago and she was eventually diagnosed with Cushing’s Disease (see my Syndrome blog).  She has previous issues with pituitary, parathyroid and recently diagnosed with a Thymic NET.  She believes there is a potential connection with MEN1 (see my blog Running in the Family) but this is currently dismissed by her physicians.

There is potentially a new problem outlined in her latest blog which inspired me to write this post.  She has a very strange symptom in that she can smell smoke despite there not being any smoke and this happens in different locations.  Her latest blog is her story about this symptom and what happened next.  Excuse the language but I would be frustrated too!  Read the blog ‘Where there is smoke …..’ by ‘clicking here’.

I wish Shannon well and hope she gets some answers – no more tumours please.  You are a survivor!

Thanks for listening

Ronny

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Running in the Family – Multiple Endocrine Neoplasia (MEN)


CancerDNAMarkers__0327

We all know that Neuroendocrine Tumours (NETs) and their syndromes are complex but there is even more complexity to be found in a group of related disorders known as Multiple Endocrine Neoplasia (MEN).  I recommend all NET patients should try to understand the basics of MEN and vice versa, particularly as both conditions seem to come with a plethora of endocrine related effects.

Overview

MEN patients will normally have a tumour in at least two endocrine glands – thus the terms ‘Multiple’ and ‘Endocrine’ (tumours can also develop in other organs and tissues).  Neoplasia is just another name for tumour and these can be non-cancerous (benign) or cancerous (malignant) with the potential to metastasize.

MEN syndromes can comprise varying combinations of tumours and many will be aware of the tumour risks from family knowledge.  So putting the heredity aspects to one side, it’s potentially an extremely challenging surveillance and subsequent diagnostic scenario if (and when) these risks are realised.  To add to the complexity, some of the associated tumours can be sporadic (non hereditary) classic Neuroendocrine Tumours in various locations.

MEN Types

MEN is actually an umbrella term for a number of types (syndromes) of the disease – MEN1, MEN2a and 2b (2b was formerly MEN3). There’s a new kid on the block called MEN4 which is extremely rare.

In the most basic of terms regarding the relationship with tumours:

MEN1 seems to be centred on tumours of the parathyroid glands, the pituitary gland, and the pancreas (the 3 P’s).

MEN2a mainly focuses on medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia or adenomas (causing hyperparathyroidism), and occasionally cutaneous lichen amyloidosis.

MEN2b  medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, and often a marfanoid habitus and other skeletal abnormalities.

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. Also referred to as MENX Possible association with tumors of the adrenals, kidneys, and reproductive organs.

What is particularly distinctive with MEN is that they are inherited disorders (familial).  That means that they can be passed down in families, with each child of an affected parent having a 1 in 2 or 50% risk of inheritance. Consequently genetic screening/testing is normally undertaken in established MEN families and those at risk of MEN.

Associated Issues

You may also have heard of other rare NETs with a familial aspect, in particular Pheochromocytomas (adrenal gland tumours) and Paragangliomas (outside the adrenal gland),  Not all are inherited and I mention them because of the connection with MEN2a and 2b.

Further information

I’m grateful to my friend and MEN patient Linda Hageman for supporting my blog activities and also for allowing me to join the AMEN support group to learn more.  This is one of the friendliest and well run support groups I’ve seen.  On this site, you will find Dr Mark Lewis, an Oncologist and MEN patient who supports Linda (who is a Nurse) with a ‘Ask the Doctor’ section on their website.

There are other organisations including one specifically for Pheochromocytomas and I’m grateful to Jennifer Shepard for featuring my nutrition blog series.

Complex area.

You may also enjoy my article on Genetics and Neuroendocrine Cancer.

Thanks for reading

Ronny

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Neuroendocrine Cancer Syndromes – Early Signs of a Late Diagnosis

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

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

It’s not all about Carcinoid Syndrome!

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

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

Functional / Non-Functional

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

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

Syndrome and Tumors – ‘Chicken or Egg’ ?

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

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

Major NET Syndromes  

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

see Genetics and Neuroendocrine Tumors

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

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

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

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

SDHx mutations/Hereditary pheochromocytoma/paraganglioma syndromes

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

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

Summary

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

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

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

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

Neuroendocrine Cancer – shh! Can you hear it? 

Thanks for reading

Ronny

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