Neuroendocrine Cancer: Fibrosis – an unsolved mystery?

Background

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

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

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

The mesentery and retroperitoneum areas

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

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

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

Metastatic-carcinoid-tumor-to-the-root-of-the-mesentery-arrow-causing-typical — Metastatic Neuroendocrine Tumor to the root of the mesentery (arrow) causing typical circumferential desmoplastic

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

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

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

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

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

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

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

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

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

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

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

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

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

What happened to me?

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

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

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

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

Summary

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

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

Neuroendocrine Cancer is normally slow growing BUT …..

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“What are you doing this afternoon”

Eight years ago today, I was sat in front of a secondary care consultant, his speciality was colorectal. I asked specifically for this consultant for two reasons, firstly, he carried out a colonoscopy some 20 months previously which turned out to be negative. Secondly, my GP had referred me to the iron deficiency anaemia clinic, and they wanted to do ….. a colonoscopy. I changed that plan because this “non-issue” was dragging on; quite frankly I wanted it to be resolved quickly, and I wanted it to be resolved in my favour – after all, I wasn’t actually ill!

Rewind two months, I had an incidental set of blood tests ordered by a nurse following a routine visit to my local medical centre (……. “I think I’ve lost a bit of weight“). My haemoglobin was low (even lower on repeat testing). The GP compared my results to someone in their eighties with malnutrition. In hindsight, I should have been alarmed by that statement but instead I went on holiday to Barbados. Apparently low haemoglobin is a sign of iron deficiency anaemia. I suspected it would pass, either my blood results would revert to normal naturally, or they would after a prescription for some pills. That’s what normally happens, isn’t it? I was so indifferent to the issue, I even delayed the blood tests by three weeks.

Back to 8th July 2010 ….I hadn’t really given him many clues but within minutes of chatting with the secondary care consultant (who was armed with the results of the negative colonoscopy test), he said “what are you doing this afternoon“. I had no hesitation in saying “whatever you want me to do“. I’m still not getting it as I saw this as a chance to get an all clear, get some pills, get back to normal. To cut a long story short, the results confirmed I had a metastatic cancer. If you can see it, you can detect it.

Following the scan results, I had a dozen other tests to narrow it down to Neuroendocrine Cancer (eventually confirmed by biopsy). During these 2 weeks of tests, I finally confessed for the first time that I had been experiencing facial flushing and intermittent diarrhea. In those days, I wasn’t really in tune with my body.

I had been sitting on a beach in Barbados sipping piña coladas with my wife and neither of us had any inkling that I had a serious life threatening illness and that it had been growing inside of me for some years. Slow but sneaky? You betcha. They did some damage too – check out my treatment summary here.

I remain thankful to all those involved in the triggering of my ‘incidental’ diagnosis. The Nurse who ordered the ‘just to be sure’ blood tests, the GP who immediately referred me to secondary care (increased my chances of being diagnosed with cancer), the secondary care specialist who was instrumental in getting to the bottom of the problem in double-quick time.

My intransigence, denial and withholding vital symptoms from the doctors didn’t really help – there’s a lesson for all there.

You can hear me talk about my diagnosis by clicking here

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Ronny

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Neuroendocrine Cancer: To cut or not to cut?

OPINION – nothing in here should be taken as advice from the author.

On paper, surgery remains the only potentially ‘curative‘ option for Neuroendocrine Tumours (NETs) but there are stage, grade and anatomical constraints to that opinion. Many people get ‘twitchy’ about any inference of the ‘C word’ (cure) but our most eminent NET specialists use the term frequently including in the major treatment guidelines.

I use the word ‘curative’ with some reservations because for many who are diagnosed at an advanced stage, surgery will not cure but will debulk or cytoreduce as much tumour as possible in order to palliate symptoms and improve quality of life. This is a big deal because NETs is one of a small number of cancers where debulking surgery can often provide a survival advantage for metastatic cases. One of the reasons it’s a big deal is because with more aggressive cancers at an advanced stage, surgery just might not be offered. It follows that surgery is most likely adding to the fairly decent NETs survival statistics, including for those with metastatic disease at diagnosis. More on this below.

That’s a fairly simplistic explanation on behalf of surgery. However, as we all know, nothing in Neuroendocrine Cancer is simple. There are always a number of factors involved and every decision can in some way be on an individual basis. There are guidelines for treatment of most types of NETs but ……. they are just that – guidelines. NET Centres and NET Specialists are encouraged to use these guidelines, for example, a European Centre of Excellence has ENETS Guidelines. There is a North American equivalent set published by NANETS and NCCN have a decent complementary set. The UK and Ireland guys (UKINETS) also published a set although many UK centres are ENETS accredited.

Whether to cut or not to cut (or watch and wait then cut if necessary) and the sequencing of treatments is a really difficult issue for NET specialists. I quite liked watching these two video clips and they cover this issue quite nicely including some interesting abdominal challenges in surgery from known NET Specialists – these short video sessions are highly recommended:

a. Risk Stratification and Management of NETs – click here

b. Surgical Considerations for NETs – click here

Surgery can sometimes be a tough call (……to cut or not to cut?)

It is an area where I have some sympathy for physicians and surgeons who sometimes have tough decisions to make. Surgery is risky, particularly where people are presenting in a weak condition, perhaps with very advanced disease, secondary illness and comorbidities. I also suspect age is a factor (I was surprised to find myself considered ‘young’ at 55). Physicians and surgeons need to weigh up these risks and the consequences of the surgery against a ‘watch and wait’ or alternative non-surgical approach. This would normally be discussed via a ‘Tumor Board’ or Multi-Disciplinary Team (MDT) meeting. However, and although imaging helps, the situation is not really 100% clear until the surgeon ‘gets inside’. Remember, all physicians and surgeons are bound by the ‘Hippocratic oath’ of “Do no harm“. Sometimes with NETs, it’s a tough call not only before they go inside but whilst they’re inside.

Surgery should be a carefully considered treatment (…..think before cutting?)

I read many stories from many different parts of the world and I also hear them from people who contact me privately on a daily basis. Some of them are perplexed why they are not receiving surgery and some are not entirely happy with the surgery they received. Many are perplexed by different advice from different doctors. I find it very difficult to respond to many. My most frequent answer is “ask your doctor” but I’m normally pretty helpful with the sorts of questions to ask.

One thing which tends to surprise people is speed – or lack of it! With lower grade NETs, the extent of the tumour (stage), its metastases, histological grade and secretory profile should be determined as far as possible before planning treatment. I like to remind people that in 2010, it took from 26 July to 9 Nov before my body saw a scalpel. With Grade 1/2 well differentiated NETs, you can often get away with that gap. Sometimes when you are diagnosed with NET, it’s a case of ‘hurry up and wait’.

Back to the guidelines, of course most people will probably fit reasonably well into the relevant guidelines flow chart. A very generic example here (not for active use please, your area may have an alternative based on availability of treatments etc):

algorithm-ukinets-page-2-gutjnl-2012-january-61-1-6-f2-large — Very generic treatment algorithm UKINETS – Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (NETs) Gut 2012;61:6-32. For example purposes only please.

If you search long and hard, you will find articles about whether to “cut or not to cut”. Not just a dilemma for NETs but also for many cancer types. During my research, I found there’s some overlap between this conundrum and the issue of “overdiagnosis”. By “overdiagnosis”, I mean the unnecessary declaration and treatment of something which would probably not harm a person whilst they live. This is a bit of a modern phenomena as diagnostic tools and screening programmes become more sophisticated and more sensitive …..something to consider with Ga68 PET scans as they are more widely used. If you search for ‘overdiagnosis’ you will see many articles, in particular (and as an example), with many Thyroid diagnoses. In another example, I read an article about Rectal cancer where the author suggested a ‘wait and see’ approach might be better for most. Worth adding at this point that many autopsies show up NETs in areas such as the appendix (…..more often than you think) – check out my article “Benign vs Malignant” and The Invisible NET Patient Population. When I attended ENETS 2017 and 2018, I heard many ‘experts’ talk about conservative approaches. However, I also heard many talk about aggressive approaches. Another term I see a lot is “one surgeon’s inoperable is another’s operable”.

Timing of Surgery (……to cut now, to cut later?)

Following on from the scenario above, timing of surgery can be another factor in a ‘watch and wait’ situation. I guess this might be something in the back of the minds of more cautious doctors when faced with a rather indolent and very slow growing Neuroendocrine Tumour. For some this can be a sensible thing – ‘kicking butt’ in a surgical context is sometimes the wrong approach. The worry is that if they are not a NET specialist, they may not fully understand the vagaries of neuroendocrine tumor behaviour (i.e. they all have malignant potential – WHO 2010/2017). We’ve all heard the stories of people being told it’s not cancer, right? Please note my article Benign vs Malignant. However, you may be interested in this post from someone who is one of the most experienced NET surgeons on the planet. Dr Eric Liu talks quite candidly about the ‘timing’ of surgery suggesting a ‘watch and wait’ approach in certain scenarios.

Of course cutting now might actually be a pre-emptive measure. For example, if physicians can see a growth which is critically placed close to an important structure such as a blood vessel or the bile duct or bowel. Even if the disease cannot be cured, removing the tumour may prevent problems in the future by removing disease from key areas before the vital structure has been damaged or blocked. For example, my surgeon conducted a high risk operation on some desmoplasia (serotonin fibrosis) which had encircled my aorta and cava almost occluding the latter. There’s an excellent surgery pamphlet from NET Patient Foundation and I strongly recommend a read as it’s an experienced surgeon’s approach to surgery with NETs (actually written by my own surgeon Mr Neil Pearce!). Click here to read it.

One NET centre in USA has published very detailed surgical statistics indicating that surgical cytoreduction in NET patients has low morbidity and mortality rates and results in prolonged survival. Their conclusion went on to say “We believe that surgical cytoreduction should play a major role in the care of patients with NETs”. You can read the extract from this document by clicking here. Authors: Woltering et al.

Was Steve Jobs a smart guy who made a stupid decision when it came to his health? It might seem so, from the broad outlines of what he did in 2003 when a CT scan and other tests found a cancerous tumour in his pancreas. Doctors urged him to have an operation to remove the tumour, but Mr. Jobs put it off and instead tried a vegan diet, juices, herbs, acupuncture and other alternative remedies. Nine months later, the Neuroendocrine Tumour had grown. Only then did he agree to surgery, during which his doctors found the cancer had spread to his liver. The rest is summarised in my article Steve Jobs.

Summary

This is a difficult subject and no one size fits all. Treatment for NETs can be very individual including surgery. I guess you need to be comfortable with your team. I was lucky, in that I lived close to a NET Centre. I was referred to their surgical team once my staging and grading were complete and I was stabilised on somatostatin analogues (carcinoid syndrome under control). I realise it’s difficult for many but I always say to people who make contact, it’s best if you can be seen by a NET centre or an experienced NET specialist – at least be guided by one if not possible or practical. Personally, I think the surgeon’s experience in dealing with NETs is really important. But even experienced NET centres/specialists have to make tough calls.

You may benefit from my 10 Questions article which also has links to NET Specialists.

Thanks for reading

Ronny

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Does your body now have an extra organ? The MESENTERY

One of the very first words I heard at diagnosis was the word “Mesentery“. In the news today is the announcement that is now might just be a new organ following accepted findings from research conducted in the University of Limerick Ireland. I always knew it was something which held the small and large intestines in place within the abdomen so like many others, I just thought it was some kind of membrane type structure and I also knew there was some kind of interaction with the peritoneum, another word which I was to become familiar with.

This is an important area for NET patients as many will have mesenteric involvement in their disease. I’ve read reports of a primary mesenteric tumour although it’s mainly a site for secondary disease (metastasis). It’s no surprise when you consider the geography – the small and large intestines are inextricably linked to this new organ. There is pancreatic involvement too. The mesentery contains many lymph nodes (the main place for metastasis for small intestinal NETs and other types) and has important blood vessels adding complexity to surgery. It’s also a place where there’s likely to be fibrotic reactions (desmoplasia) from the excess release of serotonin which can also complicate surgery.

When I check my own records, I can see statements such as “mesenteric disease”, “bulky mesenteric nodes”, “further nodal disease situated on the superior mesenteric artery and vein” and “dense retroperitoneal reaction encircling his aorta and cava from just below the level of the superior mesenteric artery”. When I also look at the post surgical reports, I can see that I had something called a “mesenteric root dissection” which needed a “superior mesenteric vein reconstruction”.

So there you have it, the anatomic description that had been laid down over 100 years of anatomy was incorrect. This organ is far from fragmented and complex. It is simply one continuous structure. According to the article I read, medical students started being taught that the mesentery is a distinct organ and the world’s best-known series of medical textbooks, Gray’s Anatomy, has even been updated to include the new definition. Finally, so what you might be thinking? Here’s a quote from the person who led the work:

“The next step is the function,” Coffey explained. “If you understand the function you can identify abnormal function, and then you have disease. Put them all together and you have the field of mesenteric science … the basis for a whole new area of science.”

Reference material:

http://www.sciencealert.com/it-s-official-a-brand-new-human-organ-has-been-classified

http://www.chicagotribune.com/lifestyles/health/ct-mesentery-new-human-organ-20170104-story.html

https://www.ul.ie/research/blog/irish-surgeon-identifies-emerging-area-medical-science

Thanks for listening

Ronny

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Serotonin – the NET effect

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

Background

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

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

Serotonin and NETs

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

Where does Serotonin come from?

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

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

While serotonin cannot cross the blood-brain barrier, tryptophan can, and once there, almost all of it is converted to serotonin. Unlike, peripheral setotonin where only a small percentage is used to generate serotonin. Just to emphasise that NET dietitians do not say to avoid foods containing tryptophan other than at the time of marker testing (see below and nutrition Blog 4). When you look at the role in brain serotonin, this might have an adverse effect.

Serotonin Inhibitors

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

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

Serotonin and the Brain

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

“Cancer anger” is a normal response to fear, despair and grief – a range of feelings which cancer brings into our lives. It can show as frustration, irritability, emotional withdrawal or aggression. You can feel it whether you have been diagnosed or you are a relative or friend. Cancer anger can happen at any stage of the illness, even years after treatment. I know that many people with cancer suffer from depression, anxiety and anger but they do not all have serotonin-producing tumours. What they do have is a life threatening and/or life changing condition which is bound to have an effect on mind as well as body. Hormones including Serotonin are natural substances found in the body and not just there to service NETs.

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

My simple way of thinking about such things as outlined above, is that low levels of tryptophan in the brain might be contributing to low levels of serotonin in the brain. To clarify that, I researched the reasons why there could be low serotonin in the brain. First, let’s dismiss any connection that the type of anti-depressant called Selective serotonin reuptake inhibitors (SSRIs) is involved. It’s thought that SSRIs work by increasing serotonin levels in the brain. Serotonin is a neurotransmitter (a messenger chemical that carries signals between nerve cells in the brain). We already discussed that it’s thought to have a good influence on mood, emotion and sleep. After carrying a message, serotonin is usually reabsorbed by the nerve cells (known as “reuptake”). SSRIs work by blocking (“inhibiting”) reuptake, meaning more serotonin is available to pass further messages between nearby nerve cells. So tryptophan or peripheral serotonin are not really involved.

It would be too simplistic to say that depression and related mental health conditions are caused by low serotonin levels (in the brain), but a rise in serotonin levels (in the brain) can improve symptoms and make people more responsive to other types of treatment, such as Cognitive Behaviour Therapy (CBT). It’s also too simple to suggest that NET patients get depression and anxiety due to all the “hormones” these tumours produce. Of course hormones can be involved in depression and anxiety but hormones aren’t their just for NET patients. Cancer patients without hormone secreting tumours also get anxiety and depression so it’s possible that NET patients can get depression and anxiety in the same way.

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

Measuring Serotonin levels

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

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

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

Serotonin Video with myself and Dr Mike Morse

I made a video in 2019 with Dr Mike Morse sponsored by Lexicon Pharmaceuticals, Inc. It’s all about Carcinoid Syndrome with a slant towards hormones, in particular Serotonin. Entitled “Likely Suspects: How Hormones May Lead to Carcinoid Syndrome – What People Living With Carcinoid Syndrome Need to Know”

You need to register to watch although some of you will already be registered and just need an email to login to see the this webcast. The one I’m featured in is the latest in a series on the subject and I’d like to break the record for views please! Please help me achieve this 💙 I would also love to get your feedback and sincerely hope you will find the time to listen in. Please also find the time to complete the survey at the end. Thanks

Click on the link here: www.CarcinoidWebcast.com

Don’t forget to press the play button and ensure your sound is turned up, particularly on mobile devices.

Summary

I did say it was a difficult jigsaw!

Thanks for reading

Ronny

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

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Surgery is risky but so is driving a car

I enjoyed reading the recent blog written by Dr Eric Liu entitled The Complications of Surgery. In his article, Dr Liu, himself a surgeon, explains that surgery comes with risks and patients should be made aware and able to discuss these risks with their doctors.

This got me thinking about my own experience which goes back to the autumn (fall) of 2010 when I first met my surgeon. At that time, there were a few articles about whether surgery or biochemistry was the best treatment for certain types, grades and stages of Neuroendocrine Tumours (NETs). Another difficult issue for NETs can be the decision to cut or not to cut – as outlined in this article.

NETs are not that much different to other Cancers in this respect – there is always a balance between maximizing QoL and extending life. I was very lucky that I lived on the south central coast of England because the local Neuroendocrine Cancer expertise was (and still is) one of the best in the country. After initial diagnosis, I was followed up with more specialist tests and then offered multimodal treatment including surgery. The risks of surgery were always fully explained to me – in any case I had to sign the consent forms where they were listed! Not sure why but I couldn’t help laughing (probably nervously!) when I noted that ‘death’ was one of the risks. It didn’t put me off and I told him to “get on with it“.

What also caused me to smirk was my surgical labelling as a “young, slim and fit man”. I was then 55 years old, slightly heavier than I thought I should be and although I had been fit for most of my life, I wasn’t that fit at the time of diagnosis. However, my surgeon was clearly doing his own risk assessment and I seemed to tick all the boxes to be able to withstand what was to be a fairly rigorous 9 hours on his table. However, it was clear to me that age, weight/BMI and level of fitness are risk factors for surgery.

I don’t want to get too deep into the moral and ethical dilemmas faced by surgeons but Dr Liu’s very honest blog and my own patient experience, highlights the need, not only for a two-way conversation between surgeon and patient, but also the need for informed consent.

I clearly survived but to be honest, it was a tough period. During my first major operation, some risks were realised resulting in a much longer stay in hospital and some effects are still present today. Many of the risks involved the dissection of desmopasia (fibrosis from NETs) around the aortic area (read more here). The planned 10 day stay was extended to 19 due to a suspected infection (elevated white blood cell count) and a post operative seroma (a pool of ‘liquid’) which was causing some pain. The white blood cell count eventually settled down but for the post operative seroma, I was subjected to a CT guided needle aspiration which was great fun to watch. Fortunately for this short notice and risky procedure, I was in the hands of one of the best Interventional Radiologists in the country. Some six weeks after discharge, a follow-up scan spotted Pulmonary Emboli (blood clots) on one of my lungs and I’ve been on blood thinning treatment ever since. I returned to the same surgeon’s table 4 months later for a liver resection using laparoscopic techniques (keyhole). Again the risks were explained but it was a breeze and I was home after 6 days.

Yes, surgery comes with risks – sometimes they are realised, sometimes they are not. Action planning to counter the common risks if realised is no doubt sensible (and I suspect already part of surgical procedures and training). However, as Dr Liu says, there can be unforeseen circumstances in the course of the operation and recovery.

Almost 8 years on from diagnosis, I’m certain the two major surgeries have played a big part in keeping me alive and as well as can be expected. For me surgery remains the The Gift that keeps on Giving. If you have time, I also published a blog Surgery for NETs – Chop Chop! which contains links to surgeons talking about surgery for Neuroendocrine Cancer. There are also links to some surgical videos – I personally found them fascinating.

Thanks for reading

Ronny

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

Disclaimer

My Diagnosis and Treatment History

Most Popular Posts

Sign up for my twitter newsletter

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