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.
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:
When should genetic testing be performed in patients with neuroendocrine tumours?
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:
One of the most controversial aspects of Neuroendocrine Neoplasms, in particular low grade Neuroendocrine Tumours (NETs), is the ‘benign vs malignant’ question. It’s been widely debated and it frequently patrols the various patient forums and other social media platforms. It raises emotions and it triggers many responses ….. at least from those willing to engage in the conversation. At best, this issue can cause confusion, at worst, it might contradict what new patients have been told by their physicians (….or not been told). I don’t believe it’s an exact science and can be challenging for a NET specialist let alone a doctor who is not familiar with the disease.
NANETS Guidance talks about the ‘…heterogeneous clinical presentations and varying degrees of aggressiveness‘ and ‘…there are many aspects to the treatment of neuroendocrine tumours that remain unclear and controversial‘. I’m sure the ‘benign vs malignant’ issue plays a part in these statements.
In another example, ENETS Guidance discusses (e.g.) Small Intestine Tumours (Si-NETs) stating that they ‘derive from serotonin-producing enterochromaffin cells. The biology of these tumors is different from other NENs of the digestive tract, characterized by a low proliferation rate [the vast majority are grade 1 (G1) and G2], they are often indolent’. However, they then go on to say that ‘Si-NETs are often discovered at an advanced disease stage – regional disease (36%) and distant metastasis (48%) are present‘. It follows that the term ‘indolent‘ does not mean they are not dangerous and can be ignored and written off as ‘benign’. This presents a huge challenge to physicians when deciding whether to cut or not to cut.
To fully understand this issue, I studied some basic (but very widely accepted) definitions of cancer. I also need to bring the ‘C’ word into the equation (Carcinoid), because the history of these tumours is frequently where a lot of the confusion lies. The use of the out of date term by both patients, patient advocates and doctors exacerbates the issue given that it decodes to ‘carcinoma like‘ which infers it is not a proper cancer. See more below.
Let’s look at these definitions provided by the National Cancer Institute. Please note I could have selected a number of organisations but in general, they all tend to agree with these definitions give or take a few words. These definitions help with understanding as there can be an associated ‘tumour’ vs ‘cancer’ debate too.
Cancer – Cancer is the name given to a collection of related diseases. In all types of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues. There are more than 100 types of cancer which are usually named for the organs or tissues where the cancers form. However, they also may be described by the type of cell that formed them.
Author’s note: The last sentence is important for Neuroendocrine Tumour awareness (i.e. Neuroendocrine Tumour of the Pancreas rather than Pancreatic Cancer).
Carcinoma – Carcinomas are the most common grouping of cancer types. They are formed by epithelial cells, which are the cells that cover the inside and outside surfaces of the body. There are many types of epithelial cells, which often have a column-like shape when viewed under a microscope.
Author’s note: By definition, Carcinomas are malignant, i.e. they are without question malignant cancers. Poorly differentiated Neuroendocrine Neoplasms are deemed to be a ‘Neuroendocrine Carcinoma’ according to the most recent World Health Organisation (WHO) classification of Neuroendocrine Tumours (2017) and ENETS 2016 Guidance. You will have heard of some of the types of Carcinoma such as ‘Adenocarcinoma’ (incidentally, the term ‘Adeno’ simply means ‘gland’). It follows that Grade 3 Neuroendocrine Carcinomas (NEC) are beyond the scope of this discussion.
Malignant – Cancerous. Malignant cells can invade and destroy nearby tissue and spread to other parts of the body.
Benign – Not cancerous. Benign tumors may grow larger but do not spread to other parts of the body.
Author’s Note: This is a key definition because there are people out there who think that low grade NETs are not cancer.
Tumour (Tumor) – An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancerous), or malignant (cancerous). Also called Neoplasm.
Author’s Note: Neoplasm is an interesting term as this is what is frequently used by ENETS and NANETS in their technical documentation, sometimes to cover all Neuroendocrine types of cancer (Tumor and Carcinoma). It follows that a malignant tumour is Cancer. The term “Malignant Neuroendocrine Tumour” is the same as saying “Neuroendocrine Cancer”
Neuroendocrine Tumours – Benign or Malignant?
Definitions out of the way, I have studied the ENETS, UKINETS and NANETS guidance both of which are based on internationally recognised classification schemes (i.e. the World Health Organisation (WHO)).
In older versions of the WHO classification schemes (1980 and 2000), the words ‘benign’ and ‘uncertain behaviour’ were used for Grades 1 and 2. However, the 2010 edition, the classification is fundamentally different (as is the recent 2017 publication). Firstly, it separated out grade and stage for the first time (stage would now be covered by internationally accepted staging systems such as TNM – Tumour, (Lymph) Nodes, Metastasis). Additionally, and this is key to the benign vs malignant discussion, the WHO 2010 classification is based on the concept that all NETs have malignant potential. Here’s a quote from the UKINETS 2011 Guidelines (Ramage, Caplin, Meyer, Grossman, et al).
Tumours should be classified according to the WHO 2010 classification (Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010). This classification is fundamentally different from the WHO 2000 classification scheme, as it no longer combines stage related information with the two-tiered system of well and poorly differentiated NETs. The WHO 2010 classification is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential.
The guidance in 2017 WHO reinforces this statement to include endocrine organs, including the pancreas and adrenal glands.
History lesson – Carcinoid tumours were first identified as a specific, distinct type of growth in the mid-1800’s, and the name “karzinoide” was first applied in 1907 by German pathlogist Siegfried Oberndorfer in Europe in an attempt to designate these tumors as midway between carcinomas (cancers) and adenomas (benign tumors).
The word ‘Carcinoid’ originates from the term ‘Carcinoma-like’. ‘CARCIN’ is a truncation of Carcinoma. ‘OID’ is a suffix used in medical parlance meaning ‘resembling’ or ‘like’. This is why many people think that Carcinoid is not a proper cancer.
The situation is made even more confusing by those who use the term “Carcinoid and Neuroendocrine Tumors” inferring that it is a separate disease from the widely accepted and correct term ‘Neuroendocrine Tumor’ or Neuroendocrine Neoplasm. A separate discussion on this subject can be found in this post here. I encourage you to stop using the term ‘Carcinoid’ which is just perpetuating the problem.
How are NENs Classified?
If you read any NET support website it will normally begin by stating that Neuroendocrine Tumours constitute a heterogeneous group of tumours. This means they are a wide-ranging group of different types of tumours. However, the latest WHO classification scheme uses the terms ‘Neuroendocrine Tumour’ for well differentiated Grade 1 (low-grade), Grade 2 (Intermediate Grade) and Grade 3 (High Grade) NET; and ‘Neuroendocrine Carcinoma’ (NEC) for poorly differentiated tumours which are by default grade 3 or high grade. They also use the term ‘Neoplasm’ to encompass all types of NET and NEC. So Grade 1 is a low-grade malignancy and so on (i.e any grade of NET is a malignant tumour). You may benefit from reading my blog article on Staging and Grading of NETs as this is also a poorly understood area.
Can some NETs be Benign?
By any accepted definition of cancer terms, a tumour can be non-cancerous (benign) or cancerous (malignant). This is correct for any cancer type. For example, the word is used in the 2016 version of Inter Science Institute publication on Neuroendocrine Tumors, a document I frequently reference in my blog. For example, I’ve seen statements such as “These tumors are most commonly benign (90%)” in relation to Insulinoma (a type of Pancreatic NET or pNET). Ditto for Pheochromocytoma (an adrenal gland NET). Adrenal and Pituitary ‘adenomas’ are by definition benign (adenoma is the benign version of Adenocarcinoma). And I note that there is a ‘benign’ code option for every single NET listed in the WHO International Classification of Diseases (ICD) system.
The ‘BUT‘ is this – all WHO classification systems are based on the concept that NETs always have malignant potential. The WHO 2017 classification update confirmed this thinking by adding endocrine organs including the pancreas and adrenal glands.
Can Tumours be Malignant or become Malignant?
Using the definition above, if a tumour invades and destroy nearby tissue and spread to other parts of the body, then it’s malignant (i.e Cancer). However, there’s a reason why the WHO declared in 2010 that all NETs have malignant potential (as amplified in WHO 2017). It may not happen or it may happen slowly over time but as Dr Richard Warner says, “they don’t all fulfill their malignant potential, but they all have that possible outcome”. Thus why ongoing surveillance is important after any diagnosis of Neuroendocrine Tumour of any grade or at any stage. Dr Lowell Anthony, a NET Specialist from the University of Kentucky explains this much better than I can – CLICK HEREto hear his two-minute video clip. This issue even caused confusion with doctors, some of whom still think a Stage 4 NET is still benign. Not only is this very insensitive to the patient concerned but it also goes against all the definitions of ‘benign’ and ‘malignant’ that exist in authoritative texts.
This was a difficult piece of research. I do believe there are scenarios where NETs will be benign and probably never cause the person any real harm (e.g. many are found on autopsies). I suspect this is the same for many cancers. However, based on the above text and the stories of people who have presented for a second time but with metastatic disease, use of the word ‘benign’ is probably best used with great care.
I would certainly (at least) raise an eyebrow if someone said to anyone with any NET tumour, “you don’t need any treatment or surveillance for a NET”; or “it has been cured and no further treatment or surveillance is required”. Particularly if they are not a NET specialist or a recognised NET Centre.
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.
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 LabTestsOnlinewhich 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.
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 dissimilarelements;nothaving a uniformqualitythroughout). 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.
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.
Markers for measuring Tumour bulk or load/growth prediction
Chromogranin (plasma/blood test)
Chromogranin 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:
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.
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 Serotoninalthough 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.
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)
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.
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.
Somatostatinoma – Somatostatin (plasma somatostatin like immunoreactivity)
PPoma – Pancreatic Polypeptide (PP)
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.
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.
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.
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!
This article is designed for patients to understand in a simple way and only covers the basics. If you are a medical professional, I recommend this artilcle:
Herrera-Martínez, A., Hofland, L., Gálvez Moreno, M., Castaño, J., de Herder, W., & Feelders, R. (2019). Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers, Endocrine-Related Cancer. Retrieved Apr 5, 2019, from CLICK HERE
In 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
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One of the unusual aspects of Neuroendocrine Cancer is that chemotherapy is not normally considered as a ‘standard’ treatment unlike many other cancers. One exception is high grade (Grade 3) where it is often a first and/or second line therapy. Poorly differentiated Neuroendocrine disease is normally labelled as Neuroendocrine Carcinoma (NEC) but worth pointing out there is now a Grade 3 well differentiated classification known as a ‘Grade 3 NET’ rather than Grade 3 NEC. Depending on Ki67 score, there could be differing treatment options for Grade 3 NET and Grade 3 NEC. Read more in my articles Staging and Grading and High Grade.
Many people think Chemotherapy has a short life span due to recent advances in medical science, some citing Immunotherapy as it’s replacement. However, it’s far too early to write off chemotherapy which is still used in many scenarios and remains a tool in the arsenal of cancer treatments and is predicted to do for some time yet. See more informed reporting about this below.
Which Chemo for which Neuroendocrine Cancer type and grade/differentiation?
The type of chemo or the combination of different treatments will often depend on the tumour type and anatomical location involved but may include (but not limited to): Capecitabine (Xeloda), Temozolomide (Temodal), Fluorouracil (5-FU), Oxaliplatin (Eloxatin) Cisplatin, Etoposide (Etopophos, Vepesid), Carboplatin, Streptozotocin (Zanosar). Some of these may be given as a combination treatment, e.g. CAPecitabine and TEMozolomide (CAPTEM). many as a combo treatment. There is a useful article explaining the role of Ki-67 in determining optimal chemotherapy in high grade neuroendocrine tumors.
Cytotoxic chemotherapy is often inadequate for treatment of Grade 1 and 2 (well differentiated) Neuroendocrine tumours which have a low proliferation index. Chemotherapy does not appear to like their slow cytokinetic growth. However, it tends to work better on certain parts of the anatomy than others, e.g. pancreatic NETs and Lung NETs. Of interest is a statistic from NET Research Foundation indicating that 23% of patients who were to be prescribed chemo had their treatment changed to a non-chemo option following a Ga68 PET scan. Read more here.
For second line therapy (including for well differentiated NETs where other conventional treatments are not working), chemo may be given. These include (but not limited to) Capecitabine, Temozolomide, Bevacizumab, Xelox, Folfox. There are other specialist chemos for Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).
‘Horses for Courses’ – Chemo is sometimes used for well differentiated lower grade NETs.
There’s a myth that circulates the NET patient forums along the lines of “chemotherapy does not work for NETs“. That’s not entirely true but most will not get chemotherapy and this can often lead to confusion in those with Stage 4 cancer when asked by others why they are not receiving chemo.
Capecitabine plus Temozolomide (CAPTEM for short) is fast becoming the standarad chemotherapy treatment when it is required with certain lower grade NETs. Dr Robert Fine says the results of the CAPTEM trial showed “tremendous responses in every neuroendocrine tumor”. The treatment elicited a response rate of 45% and a stable disease rate of 52% including those with certain types of NETs and pituitary tumours – types of neuroendocrine tumour that are notoriously ‘chemoresistant’. You can read more about this here (click here) and you can also listen to Dr Fine talking about this on a short You Tube video clip – (click here). Clearly it’s true that it’s not going to work for all.
Other CAPTEM Resources:
There’s a very interesting report on the use of CAPTEM in NETs – (click here)
In Australia, they’re also using a combo treatment of chemo (CAPTEM) and PRRT – I blogged about this click here.
There’s also a useful surgical technique which includes the use of intra-operative chemo, known as “Chinese Dumplings” – I wrote about this click here.
My Oncologist did mention Chemotherapy on my initial meeting, that was a shock and realisation I had something serious. However, that never transpired but I was once scheduled to have a chemo-embolisation (or TACE, Trans-arterial Chemo Embolisation). Clearly TACE is more targeted than conventional and generally systemic chemotherapy techniques. Perhaps that my Oncologist actually meant. The chemo-embolisation never transpired either (long story).
Chemotherapy vs Targeted Biological Agents and Somatostatin Analogues
I often see people describing Somatostatin Analogues (Lanreotide/Octreotide), Afinitor (Everolimus) and Sutent (Sunitinib) as chemo but that’s isn’t technically correct, and I’ve yet to find a NET Specialist or a NET Specialist Organisation who classifies these drugs as chemo. See my article “Chemo or not Chemo” (click here).
Future of Chemo?
A lot is written about how much longer chemo will be around. It gets a bad press – I suspect mainly due to the side effects. There are suggestions that it will eventually be replaced by Immunotherapyand other treatments downstream. However, immunotherapy is really still in its infancy and there remains a lack of long term data on success rates and side effects. I suspect chemo will be around for a while longer, particularly for cancers where it has a track record of curing according to ASCO. Very recently (June 2018), cancer experts said that chemo will be around for a long time yet – read more here
None of the content of this post should be interpreted as advice or a recommendation for chemotherapy. If in doubt about suitability for any form of chemo, or the type you have been prescribed, patients should seek the advice of their treating doctor or NET specialist.