Rosacea – the NET Effect


Rosacea The NET Effect

Around 2001, I started noticing some issues on my nose, particularly around the creases, an issue I still experience today.  It normally starts with a stinging feeling, an indication I’m about to experience some sort of inflammation. What eventually happens is something which looks like a ‘whitehead’ which I now know to be a ‘pustule’.  Sometimes there are multiples and most are not normally bigger than 2mm, mostly smaller. These pustules nearly always disappear within a short period of time, normally after washing/showering but they tend to leave reddish marks which eventually fade.  Very infrequently, these pustules would appear on my chin.  After 18 years of the issue, my nose is slightly discoloured and more reddish than the rest of my face.

Shortly after I started experiencing this issue, a doctor diagnosed me with ‘mild rosacea‘. If this is a correct diagnosis, then I would appear to have Subtype 2 or papulopustular (acne) rosacea (see breakdown of types below).  I also have the minor irritation of a recurrent mild eczema inside my right outer ear which has run parallel to this issue (…. spookily).

For around two years, I was treated with a mixture of low dose oral antibiotics (tetracycline) and a skin medication known as metronidazole. This did clear up the issue but it always returned and I stopped the medication opting instead for a commercial product which I find works better.  It doesn’t clear it 100% but I’ve learned to live with it and it is a long-term chronic condition.  I looked at many Rosacea sites online and none of the pictures seemed to apply to me and I agree with my diagnosing doctor in terms of a ‘mild’ version.

I worked out early on that the triggers were stress, when ‘run down’, and too long in the sun. There were possibly others.  Stress was part and parcel of the work I was involved in and it was at a time when I left my life in the military after 29 years and started a second career in industry (often I think in hindsight, I may have been overly stressed at the life change without realising it).  Without any medical input, I decided to try to make sure I got sufficient vitamins and I now appear to get less coughs and colds then I used to.  I now try to stay out of the direct sun.  Other common triggers are listed on reputable sites andinclude alcohol, hot and cold weather, exercise, hot baths and spicy foods.

What is Rosacea

A common skin condition, usually occurring on the face, which predominantly affects fair-skinned but may affect all skin types in people aged 40 to 60 years old. It is more common in women but when affecting men, it may be more severe.  It is a chronic condition, and can persist for a long time and, in any individual, the severity tends to fluctuate. Rosacea tends to affect the cheeks, forehead, chin and nose, and is characterised by persistent redness caused by dilated blood vessels, small bumps and pus-filled spots similar to acne. There may also be uncomfortable inflammation of the surface of the eyes and eyelids.  I found this site to be a very useful Rosacea reference.

Rosacea is sometimes classified into 4 subtypes that may overlap:

  • Subtype one, known as erythematotelangiectatic rosacea (ETR), is associated with facial redness, flushing, and visible blood vessels.
  • Subtype two, papulopustular (or acne) rosacea, is associated with acne-like breakouts, and often affects middle-aged women.
  • Subtype three, known as rhinophyma, is a rare form associated with thickening of the skin on your nose. It usually affects men and is often accompanied by another subtype of rosacea.
  • Subtype four is known as ocular rosacea, and its symptoms are centred on the eye area.

What causes rosacea?  

The cause of rosacea is not fully understood. Your genetics, immune system factors, and environmental factors may all play a part. Factors that trigger rosacea cause the blood vessels in the skin of the face to enlarge (dilate). The theory that rosacea is due to bacteria on the skin or in the gut has not been proven. However, antibiotics have proven helpful to treat rosacea. This is because of their anti-inflammatory effect. Rosacea is not contagious.

Why is rosacea sometimes linked to NETs?

On certain sites and in certain texts about NETs, you will see mention of Rosacea, clearly as a misdiagnosis of someone who presents with flushing.  I started experiencing the sensation of NET related flushing in late 2009/early 2010 and I can honestly say this was a totally different experience to what I had with my mild rosacea. However, I don’t have the ‘blushing’ type of rosacea and I can see the presentational similarities.

Another issue commonly reported in both conditions is small visible blood vessels on the face, known formally as Telangiectasia or informally as ‘spider veins’ or ‘broken capillary veins’. This is quite common with erythematotelangiectatic rosacea (subtype 1).  I actually have at least two of these showing and this appears to be something I’ve only noticed since NET diagnosis and only in the last few years.  Interesting it says this is something normally caused by “chronic flushing” but I wouldn’t have labelled by flushing in that way. I have not felt any flushing since late 2010 after surgery and commencement of long acting somatostatin analogues.  Unless there has been something ‘sub-clinical’ going on, I’ve veered my minor issue towards long-term but mild rosacea as the cause rather than NETs.  Telangiectasia is mentioned in many NET texts including my own article “Neuroendocrine Cancer: A Witch’s Brew of Signs and Symptoms”

Histamine if often linked to both conditions.  Read about NET related histamine here and Rosacea histamine issues here.

Summary

I’ll be honest with you, I’m actually not 100% convinced I have rosacea as it has similarities with many other skin conditions. In fact, skin issues are pretty common with NET patients, some are actually directly linked to NETs including Merkel Cell Carcinoma,  pellagra (linked to Carcinoid Syndrome) and Sweet’s syndrome (linked to Glucagonoma).  In addition, many people develop skin issues as a side effect of treatment.  Read more here.

Thanks for reading

Ronny

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

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Ronny Allan is an award winning patient leader and advocate for Neuroendocrine Cancer.

 

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Diabetes – The NET Effect


My chest infection is now settled, as too is the excitement and apprehension behind my first ever Ga68 PET – the outcome of that is still a work in progress. Earlier this year, my thyroid ‘lesion’ on watch and wait was given a ‘damping down’ with the prescription of a thyroid hormone supplement but I await a re-ignition of that small bush fire downstream.

Bubbling behind the scenes and clamoring for attention is the spiking of my blood glucose test results and I was very recently declared ‘at risk’ for diabetes One of my followers entitled a post in my group with “The hits keep coming” in reference to encountering yet another problem in the journey with Neuroendocrine Cancer. I now know how she feels, this issue is a bit of a ‘left fielder’. However, having analysed the situation and spoken to several doctors, I can now put pen to paper.

Neuroendocrine Cancer is not a household name (…… I’m working on that) but diabetes certainly is. The World Health Organisation reports that the number of adults living with diabetes has almost quadrupled since 1980 to 422 million adults. In USA, estimates from CDC stated around 10 million people diagnosed with diabetes with a further 84 million in pre-diabetes state (at risk). In UK around 3.7 million people have diabetes with about 4 times that amount ‘at risk’. It’s a growth industry (…….. but so is NETs – in the last 40 years, the incidence of NETs is rising at a faster rate than diabetes, a disease which some writers have described as an epidemic).

With those numbers, it follows that many NET patients will be diabetic before diagnosis, some will succumb to diabetes whether they have NETs or not, and some may have an increased risk of succumbing due to their treatment. Some may even be pushed into diabetes as a direct result of their NET type or treatment. It’s important to understand diabetes in order to understand why certain types of NET and certain treatments could have an involvement.

The Pancreas

For understanding of this article, it’s worth noting the pancreas has two main functions: an exocrine function that helps in digestion and an endocrine function that regulates blood sugar. I have talked about the exocrine function in relationship to Neuroendocrine Cancer at length – check out this article on Pancreatic Enzyme Replacement Therapy. In this article, I now want to cover the issues with the endocrine function and blood sugar. First a short primer on diabetes – it is necessarily brief for the purposes of this article.

 

Diabetes Primer

TypeS OF DIABETES

Type 1 and Type 2 Diabetes are fairly well-known. There’s actually more than two types, but these are the most common. Type 2 is the most prevalent with around 90% of diabetes cases. When you’ve got Type 1 diabetes, you can’t make any insulin at all. If you’ve got Type 2 diabetes, the insulin you make either can’t work effectively, or you can’t produce enough of it. Additional types may come up in the subsequent discussion.

What is the problem?

What all types of diabetes have in common is that they cause people to have too much glucose (sugar) in their blood. But we all need some glucose. It’s what gives us our energy. We get glucose when our bodies break down the carbohydrates that we eat or drink. And that glucose is released into our blood. We also need a hormone called insulin. It’s made by our pancreas, and it’s insulin that allows the glucose in our blood to enter our cells and fuel our bodies.

If you don’t have diabetes, your pancreas senses when glucose has entered your bloodstream and releases the right amount of insulin, so the glucose can get into your cells. But if you have diabetes, this system doesn’t work properly. Diabetes is associated by being overweight but there isn’t a 100% correlation with that. However, when an individual becomes overweight, there is an increase in free fatty acids in the blood stream which may contribute to reduced insulin sensitivity in the tissues, leading to increased glucose levels in blood.

Symptoms and diagnosis of Diabetes

Different people develop different symptoms. In diabetes, because glucose can’t get into your cells, it begins to build up in your blood. And too much glucose in your blood causes a lot of different problems. To begin with it leads to diabetes symptoms, like having to wee a lot (particularly at night), being incredibly thirsty, and feeling very tired. You may also lose weight, get infections like thrush or suffer from blurred vision and slow healing wounds.

I see these symptoms mentioned very frequently and normally people are trying to associate them with NETs and/or the treatment for NETs.

Diabetes diagnosis is normally triggered diagnosed based on blood tests such as fasting Blood Glucose (snapshot) and/or Glycated Hemoglobin (A1C) or HbA1C.

Complications

Over a long period of time, high glucose levels in your blood can seriously damage your heart, your eyes, your feet and your kidneys. These are known as the complications of diabetes.

But with the right treatment and care, people can live a healthy life. And there’s much less risk that someone will experience these complications.

What are the direct connections with Diabetes and NETs?

It’s not surprising that diabetes is mostly associated with Neuroendocrine Tumors of the Pancreas but there are other areas of risk for other types of NETs including to those who are existing diabetics – see below.

Surgery

The main types of surgery for Neuroendocrine Tumors of the Pancreas are Distal Pancreatectomy (tail), Sub-total pancreatectomy (central/tail), Classic Whipple (pancreaticoduodenectomy – head and/or neck of pancreas), Total pancreatectomy (remove the entire pancreas) or an Enucleation (scooping out the tumour with having to remove too much surrounding tissue). From the PERT article link above (exocrine function), you can see why some people need this treatment to offset issues of reduced production of pancreatic enzymes. The same issue can develop with a reduced endocrine function leading to the development of diabetes.

NET Syndromes

The different types of functional pancreatic NETs often called syndromes in their own right due to their secretory role. One might think that Insulinomas are connected to diabetes issues but this hormonal syndrome is actually associated with low blood sugar (hypoglycemia), although low blood sugar can turn out to be a complication of diabetes treatment.

A NET syndrome known as Glucagonoma (a type of functional pancreatic NET) is associated with high blood glucose levels. About 5-10% of pancreatic neuroendocrine tumors are Glucagonomas, tumors that produce an inappropriate abundance of the hormone glucagon. Glucagon balances the effects of insulin by regulating the amount of sugar in your blood. If you have too much glucagon, your cells don’t store sugar and instead sugar stays in your bloodstream. Glucagonoma therefore leads to diabetes-like symptoms (amongst other symptoms). In fact Glucagonoma is sometimes called the 4D syndrome – consists of diabetes, dermatitis, deep venous thrombosis (DVT), and depression.

Another functional pancreatic NET known as Somatostatinoma is prone to developing insulin resistance. Somatostatinomas produce excessive amounts of somatostatin which interferes with the insulin/glucagon function and could therefore lead to diabetes.

Diabetes caused by cancer or cancer treatment

Worth noting that this type of diabetes is sometimes known as ‘Pancreatogenic diabetes’ and this is actually classified by the American Diabetes Association and by the World Health Organization as type 3c diabetes mellitus (T3cDM) and refers to diabetes due to impairment in pancreatic endocrine function due to acute cancer and cancer treatment (and several other conditions). The texts tend to point to cancers (and other conditions) of the pancreas rather than system wide. Prevalence data on T3cDM are scarce because of insufficient research in this area and challenges with accurate diabetes classification in clinical practice. (Authors note: Slightly confusing as many text say that type 3 diabetes is proposed for insulin resistance in the brain (diabetes associated with Alzheimer’s disease).  There’s another term for a complete removal of the entire pancreas – Pancreoprivic Diabetes

Other treatment risks

Somatostatin Analogues (e.g. Octreotide and Lanreotide) are common drugs used to control NET Syndromes and are also said to have an anti-tumor effect. They are known to inhibit several hormones including glucagon and insulin and consequently may interfere with blood glucose levels. The leaflets for both drugs clearly state this side effect with a warning that diabetics who have been prescribed the drug, should inform their doctors so that dosages can be adjusted if necessary. The side effects lists also indicates high and low blood glucose symptoms indicating it can cause both low and high blood glucose (hypoglycemia and hyperglycemia). For those who are pre-diabetic or close to pre-diabetic status, there is a possibility that the drug may push blood tests into diabetic ranges.
Afinitor (Everolimus). The patient information for Afinitor (Everolimus) clearly states Increased blood sugar and fat (cholesterol and triglycerides) levels in blood: Your health care provider should do blood tests to check your fasting blood sugar, cholesterol and triglyceride levels in the blood before you start treatment with AFINITOR and during treatment with AFINITOR”
Sutent (Sunitinib). The patient information for Sutent (Sinitinib) clearly states that low blood sugar (hypoglycemia) is a potential side effect. It also advises that low blood sugar with SUTENT may be worse in patients who have diabetes and take anti-diabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with SUTENT and may need to adjust the dose of your anti-diabetic medicines.

In rare cases, certain NETs may produce too much Adrenocorticotropic hormone (ACTH), a substance that causes the adrenal glands to make too much cortisol and other hormones. This is often associated with Cushing’s syndrome. Cortisol increases our blood pressure and blood glucose levels with can lead to diabetes as a result of untreated Cushing’s syndrome.

Summary

I think it’s sensible for all NET patients, particularly those with involvement as per above and who are showing the signs of hypoglycemia and hyperglycemia, to be checked regularly for blood glucose and if necessary HbA1c. Many patient information leaflets for the common NET treatments also indicate this is necessary. Always tell your prescribing doctors if you are a diabetic or about any history of low or high blood glucose before treatment for NETs.

My brush with Diabetes (as at Jan 2019)

My blood glucose levels started to climb slightly in 2016 but HbA1c remained normal. However, an HbA1c test in early 2018 put me into pre-diabetic range (44 mmoL/moL). I explained some of the above article to my GP who is corresponding with a diabetes expert at secondary care – the expert suggested that I need to be monitored carefully as weight loss is not necessarily the best response. I have kept my NET team up to date.

At the time of updating, two separate and sequential HbA1c tests (3 month interval) came back normal at 36 mmoL/moL.  I’m pragmatic enough to know that I do not need to lose weight as one of the aims of reducing my blood glucose and HbA1c levels (something emphasised by the above mentioned diabetes specialist).

I even got on my bike to do a little bit more exercise just in case!

At this point, I cannot yet say if this is the beginning of progressive Type II diabetes or if my medication is causing these spikes in my blood glucose and HbA1c. Judging by 2 x normal HbA1c, looks like the somatostatin analogue (Lanreotide in my case) may caused a spike to a pre-diabetes score.  I will keep you posted.

Summary – if you are noticing these symptoms, get your blood sugar checked (with acknowledgement to Dr Pantalone from Cleveland Clinic)

1. You’re making more trips to the bathroom

Having to go to the bathroom more than normal, particularly at night, is a sign that your blood sugar might be out of whack.

Dr. Pantalone says one of his patients came in for a diagnosis after a family member noticed that he was using the bathroom during each commercial break when they watched TV.

2. You’re getting frequent urinary or yeast infections

When your blood sugar is high and your kidneys can’t filter it well enough, sugar ends up in the urine. More sugar in a warm, moist environment can cause urinary tract and yeast infections, especially in women.

3. You’re losing weight without trying

If you have diabetes, your body isn’t able to use glucose (sugar) as effectively for its energy. Instead, your body will start burning fat stores, and you may experience unexpected weight loss.

4. Your vision is getting worse

High sugar levels can distort the lenses in your eyes, worsening your vision. Changes in your eyeglass prescription or vision are sometimes a sign of diabetes.

5. You’re feeling fatigued or exhausted

Several underlying causes of fatigue may relate to diabetes/high sugar levels, including dehydration (from frequent urination, which can disrupt sleep) and kidney damage.

This feeling of exhaustion is often persistent and can interfere with your daily activities, says Dr Pantalone.

6. You’re noticing skin discoloration

Something that Dr. Pantalone often sees in patients before a diabetes diagnosis is dark skin in the neck folds and over the knuckles. Insulin resistance can cause this condition, known as acanthosis nigricans.

 

Thanks for reading

Ronny

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

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

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Living with Neuroendocrine Cancer – the 7 Year Itch

7 year itch

I quite like the Facebook memory thing. This morning I got a reminder of a post I made from 7 years ago whilst I was in hospital recovering from my 9 Nov surgery.  It had taken 12 days for me to feel strong enough to venture onto social media with a simple message “I’m feeling perkier”.  For those not familiar with English localisms, it just means lively, spirited, bright, sunny, cheerful, animated, upbeat, buoyant, bubbly, cheery, bouncy, genial, jaunty, chirpy, sprightly, vivacious, in fine fettle, full of beans, bright-eyed and bushy-tailed.  I guess I met some of these descriptors most of the time! I had gotten through the worst and the light at the end of the tunnel was now a faint glimmer.

I’ve recently had a ton of ‘7 years ago cancerversaries’ and there’s still a few to go! I’m currently being reminded of an issue that started just after my initial treatment and by coincidence (perhaps?) the commencement of my Lanreotide (Somatuline Autogel).  Itching!  However, for me, it’s mainly the right leg below the knee (go figure!). Much less frequently on my arms and sides.  I know many people have the same issue but no-one ever seems to find out why – I guess it’s that Neuroendocrine jigsaw thing again?

Initially, I put the issue down to Lanreotide, as this is mentioned in the side effect list on the drug instructions.  The initial connection was made because it seemed to be happening immediately after my monthly ‘dart’.  A really annoying itch mostly around my ankles and which had to be scratched!  An application of a general emollient cream for a few days seemed to do the trick and after a week it was gone (until the next injection …..). However, after a few years, I sensed the issue was drifting away from the injection cycle and adopting a different and more random pattern.  I’m also suspicious of a nutritional connection and checking my article Nutrition for NETs -Vitamins and Mineral Challenges, I can see Vit B3 (Niacin) and Vit E are mentioned in regards skin issues.  I’d be confused if this was an issue today as I now take plenty supplements to offset GI malabsorption.  However, I probably wasn’t taking sufficient between surgery and 2013 as I lacked the knowledge to do so at the time.  So nutritional deficiency remains a possibility or at least an added complication.  The most recent outbreak has unusually gone on for the last 4 weeks.

I also seem to have had an eczema type issue in my right ear and mild rosacea for more than 7 years (pre diagnosis).  As you can imagine my ‘inner detective’ is working overtime!  One thing is clear – this itchy leg issue has plagued me for 7 years.

I know that many people have real issues with rashes and skin itching, I’ve seen this so many times with some people describing it as severe.  Clearly when this is the case, a doctor’s intervention is generally required.  I’ve seen the following connections to NETs and skin issues:

Lanreotide vs Octreotide

new lanreotide
New delivery system for Lanreotide – solution remains the same

Somatostatin Analogues are the ‘workhorse’ treatments for those living with NETs, particularly where certain syndromes are involved.  So not just for classic NETs with Carcinoid Syndrome but also for treating insulinoma, gastrinoma, glucagonoma and VIPoma (all types of pNETs) and others. They are most effective if the NETs express somatostatin receptors.  They also have an anti-tumour effect but more of a slowing down of growth rather than a killing or reduction of tumour size – but there are always outliers where such effects are displayed.

Somatostatin is actually a naturally occurring hormone produced by the hypothalamus and some other tissues such as the pancreas and the gastrointestinal tract. However, it can only handle the normal release of hormones.  When NET syndromes occur, the naturally occurring somatostatin is unable to cope. The word ‘analogue’ in the simplest of terms, means ‘manufactured’ and a somatostatin analogue is made to be able to cope with the excess secretion (in most cases).

Although there is hidden complexity, the concept of the drug is fairly simple.  It can inhibit insulin, glucagon, serotonin, VIP, it can slow down bowel motility and increase absorption of fluid from the gut. It also has an inhibitory effect on growth hormone release from the pituitary gland (thus why it’s also used to treat a condition called Acromegaly). You can see why it’s a good treatment for those with NET syndromes, i.e. who suffer from the excess secretions of hormones from their NETs.  Clearly there can be side effects as it also inhibits digestive enzymes which can contribute to, or exacerbate, gastro-intestinal malabsorption.

Please note somatostatin analogues are not chemo.  There are two major types in use:

  • Octreotide – or its brand name Sandostatin.  It is suffixed by LAR for the ‘long acting release’ version.
  • Lanreotide – brand name Somatuline (suffixed by ‘Depot’ in North America, ‘Autogel’ elsewhere)

So what’s the difference between the two?

A frequently asked question. Here’s a quick summary:

  • They are made by two different companies.  Novartis manufactures Octreotide and Ipsen manufactures Lanreotide.  Octreotide has been around for much longer.
  • The long-acting versions are made and absorbed very differently.  Octreotide has a complex polymer and must be injected in the muscle to absorb properly.  Lanreotide instead uses has a novel nanotube structure and is water based (click here to see a video of how this works). It is injected deep-subcutaneously and is therefore easier to absorb and is not greatly impacted if accidentally injected into muscle.
  • Their delivery systems are mainly via injections but are fundamentally different as you can see from the blog graphic which shows the differences between the long acting release versions.  Octreotide long acting requires a pre-mix, whilst Lanreotide comes pre-filled.
  • The long-acting versions are 60, 90 and 120 mg for Lanreotide and 10, 20 and 30 mg for Octreotide.
  • Octreotide also has a daily version which is administered subcutaneously.
  • Octreotide has something called a ‘rescue shot’ which is essentially a top up to tackle breakthrough symptoms.  It is a subcutaneous injection.
  • You can also ‘pump’ Octreotide using a switched on/off continuous infusion subcutaneously.
  • Other than for lab/trial use, to the best of my knowledge, there is no daily injection, rescue shot or ‘pump’ for Lanreotide that is indicated for patient use.
  • Whilst both have anti-tumour effects, there are differences in US FDA approval: Octreotide (Sandostatin) is approved for symptom control (not anti-tumor) whereas Lanreotide (Somatuline) is approved for tumour control. However, the US FDA recently added a supplemental approval for syndrome control on the basis that it is proven to reduce the need for short acting somatostatin analogues use – read more here.  This supplementary approval followed the ELECT trial – results here.

Injection Administration

Always refer to the patient information leaflet as it is not safe to assume that all healthcare professionals are familiar with the administration.  Common issues include (but are not limited to): drug temperature requirements, injection site, pinching vs stretching skin, speed of injection.

Please note a new syringe for Lanreotide will be available in June 2019. Further information will be communicated to healthcare professionals in advance of this, to enable them to inform their patients, whom have been prescribed Lanreotide. In addition, the patient information leaflet included in the packet will have clear instructions for use. There will be a prominent yellow box located on the outer carton of the medicine, alerting healthcare professionals and patients that a new syringe is contained inside. Please note that the medicine is still the same and the formulation and storage conditions have not changed.

Here are some interesting videos showing and explaining their administration:

Administering a Somatuline Depot (Lanreotide) injection:

Administering a Sandostatin LAR (Octreotide) injection:

This link also provides guidance on the “new formulation” Octreotide.  Click here.

My own experience only includes daily injections of Octreotide (Sep-Nov 2010) and Lanreotide (Dec 2010 onwards).  I’ve also had continuous infusion of Octreotide in preparation for surgical or invasive procedures over the period 2010-2012 (i.e. crisis prevention).  You can read about my Lanreotide experience by clicking here.  If you are interested in what might be coming downstream, please see my blog entitled Somatostatin Analogues and Delivery Systems in the Pipeline’.

Injection site granulomas (lumps)

The issue of ‘granulomas‘ or ‘injection site granulomas’ seems to figure in both drugs. Gluteal injection site granulomas are a very common finding on CT and plain radiographs. They occur as a result of subcutaneous (i.e. intra-lipomatous) rather than intramuscular injection of drugs, which cause localised fat necrosis, scar formation and dystrophic calcification. But no-one seems to know why they occur with somatostatin analogues.

Personally, I find that they are more conspicuous if the injection is done slightly too high which was my initial experience and they took months to fade.  I opted to stand up for the first two injections and I attribute this decision for a slightly too high injection site.  I now lie down which is actually recommended for the smaller and thinner patient. Although the lumps have reduced in size, I have not seen a new lump for some time indicating location might have been the cause. They sometimes show up on scans.  This is not a new problem and has been highlighted for the last 10 years in academic papers.  This particular paper is useful and the conclusion confirms this is not something that should worry patients too much. Read more here

Somatostatin Analogues and raised blood sugar levels

It is well documented that both Octreotide and Lanreotide can elevate blood glucose (sugar) levels.  Read more in my article Diabetes – the NET Effect.

Somatostatin Analogues and thyroid levels

It is well documented that both Octreotide and Lanreotide can mess with thyroid hormone levels. Read more in my article on Don’t be underactive with your Thyroid surveillance.

At Home Services

Many areas have ‘at home’ services, read here to see if you qualify.

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

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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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Steve Jobs – the most famous Neuroendocrine Cancer Ambassador we NEVER had

steve jobs 2010
The last few years have reminded me that life is fragile

Steve Jobs died 5 Oct 2011.  RIP Steve, you certainly made a difference to the world of technology and that is still being felt today.  I have a number of google alerts setup and every day the emails arrive in my inbox. The longest email is always the Steve Jobs one, i.e. Steve Jobs is written about more than Neuroendocrine Cancer and other connected subjects. That’s interesting because Neuroendocrine Cancer is the type Steve had, not Pancreatic as is frequently reported.

There are huge differences between Pancreatic Cancer and Neuroendocrine Cancer with a pancreatic primary – click here to read more. 

pancreatic vs neuroendocrine

I’ve mentioned Steve Jobs a few times previously, mainly in my blog The Human Anatomy of Neuroendocrine Cancer. I wrote that blog when I was frustrated about the constant misreporting of Neuroendocrine Cancer as other types of cancer. Others included Nick Robinson (see blog The Devil is in the Detail) and Wilko Johnson (The Ecstasy of Wilko Johnson).  I’ve also suggested in my blog ‘Every Day is NET Cancer Day’ that we need high-profile patient Ambassadors and despite his death, Steve Jobs would have been quite a catch, had he been willing. Curiously, the same thing is happening with Dag Kittlaus (Siri creator) who was diagnosed with a pNET last year.  To add insult to injury, the 2018 death of Aretha Franklin is gong the same way.

A lot has been written about Steve’s cancer experience and much of it is full of ‘what ifs’. However, I’d like to focus on the facts that are known and we can be almost certain about. That said, the precise detail that we (as NET patients) might want, is probably only to be found in Steve Jobs’s medical documents. Many people say that Steve Jobs had a right to personal privacy and I agree, nothing I put here isn’t already in the public domain.

Diagnosis

How was it found?  In 2003, Steve was having a CT scan to examine his kidneys and ureter, as he had developed recurrent kidney stones beginning in the late 1990s. A suspicious lesion was spotted on his pancreas. To cut a long story short, he eventually had more specialist scans and then a biopsy which diagnosed a type of Neuroendocrine Tumour.  There are many mentions of Insulinoma, a pNET which is reported to have a 10% malignancy rate (ISI Book – Woltering et al). It isn’t clear whether Steve had any presentational symptoms of an Insulinoma at this point (i.e. hypoglycemia).  There is also some chatter online about his tumour being a Glucagonoma (another type of pNET).

Initial Treatment

Steve initially tried alternative medicine before having surgery 9 months after diagnosis. There are reports of his medical team urging surgery earlier and his biographer stated that Steve had later regretted this delay. One of his Doctors is reported to have said “Steve was a very thoughtful person. In deciding whether or not to have major surgery, and when, he spent a few months consulting with a number of physicians and scientists worldwide as well as his team of superb physicians. It was his decision to do this”.  He is reported to have gone on to have a ‘Whipple’ type operation in 2004.  It was only then, that his condition was made public.  During that operation, 3 lesions were reported on his liver.

Ongoing Treatment and Surveillance

Most NET patients enter this phase after their initial treatment, it’s also the period where you learn about the cancer and how best to live with it.  There’s not much written about Jobs’ illness between his surgery and his liver transplant but my research uncovered a useful timeline from Bloomberg and other sources:

June 12, 2005: Jobs talks about his fight with cancer during a commencement speech at Stanford University. He says he was diagnosed about a year earlier and that doctors told him he wouldn’t live longer than six months. The cancer turned out to be a form that was treatable with surgery, “and I’m fine now,” he says. Source Bloomberg.  {Author’s note:  an indication he had been told, or his doctors knew, it was a Neuroendocrine Tumor}

January 24, 2006:  Walt Disney chief executive Bob Iger knew early on that Steve Jobs’s cancer had returned and kept it a secret before it became public knowledge, a new biography of Apple’s late chief executive reveals. The day the deal was officially announced, Mr Iger said he was at Pixar’s headquarters for the ceremony when Jobs asked to go for a private walk. On a secluded part of the Californian campus Jobs put his arm around Mr Iger’s shoulder and revealed his cancer was back. “Frankly, they tell me I’ve got a 50-50 chance of living five years,” the Disney CEO quoted Jobs as saying.

2007:  Not much out there except that he was busy launching what might be regarded as Apple’s most successful and iconic product ever – the iPhone.

June 9, 2008: Jobs, while introducing the iPhone 3G at Apple’s developers’ conference, appears thinner and frail. The company blames a “common bug.”

July 21, 2008: Responding to concerns about Jobs’s appearance, Apple says he has no plans to leave the company and that his health is a private matter. Investors aren’t reassured, and the shares fall 10 percent.

July 23, 2008: The New York Times reports that Jobs has been telling associates and Apple’s board he is cancer-free. Jobs had a surgical procedure earlier in the year to address a problem that contributed to his weight loss, the newspaper reports, citing unnamed people close to the executive. The shares climb 2.6 percent.

July 26, 2008: New York Times columnist Joe Nocera writes that he spoke two days earlier on the phone with Jobs, who said his health problems weren’t life-threatening. Jobs declines to go on the record about the nature of his ailment.

Sept. 9, 2008: Jobs, introducing new iPod media players at an event in San Francisco, still looks thin. “Reports of my death are greatly exaggerated,” Jobs jokes. Munster says that while the CEO’s appearance is unchanged since June, “Just the fact that Steve Jobs was up there was a positive.”

Oct. 3, 2008: A posting on CNN’s citizen journalist Web site, called iReport.com, says Jobs has been rushed to the hospital after a “major heart attack.” The shares fall 5.4pc. The stock rebounds after Apple says the report is false.

Dec. 16, 2008: Apple says that Jobs won’t be giving his usual speech at the Macworld conference, renewing concerns about his health. Jobs had used the forum to introduce new products for 11 straight years.

Jan. 5, 2009: Jobs says he is suffering from a hormone imbalance, causing him to lose weight. Jobs vows to remain CEO during treatment. “The remedy for this nutritional problem is relatively simple and straightforward,” Jobs says in an open letter.

Jan. 14, 2009: Jobs gives up day-to-day operations to Cook until June, saying his health problems are more complex than originally thought. Jobs says he will remain involved in major strategic decisions. “I look forward to seeing all of you this summer,” he says in a letter to employees.

By this stage, his cancer is already starting to take its toll on how he looks.

The disease takes its toll over the years

Liver Transplant 2009

It is common knowledge that Jobs had a liver transplant in 2009 in Tennessee (he was on the list in California and Tennessee).  In between his Whipple and then, he appears to have lived (and worked) with his disease and it’s consequences. His issues appear to have been exacerbated by his excessive vegan diet/fads and the effects of the Whipple surgery (many of you will be aware of these effects). For example, he would spend weeks eating the same thing and then suddenly change his mind and stop eating it. He’d also go on fasts. His condition immediately prior to the liver transplant was said to be ‘poor’ and losing more weight (he had been noticeably thinner for some time).

Did Steve Jobs get ‘experimental’ PRRT?

Jobs took a second medical absence for roughly six months in 2009. It wasn’t until June 20th, two months after the fact, that the Wall Street Journal uncovered the fact that Jobs had undergone a secret liver transplant at Methodist University Hospital in Memphis, Tennessee. However, during that absence, Fortune reported Jobs also took an unpublicized flight to Switzerland to undergo an ‘unusual radiological treatment’ (PRRT) at the University of Basel for neuroendocrine cancer, according to Jerry York, the Apple director who died in March 2010.

Post-Liver Transplant

In 2010, Jobs started to feel sick again. He would lose his appetite and begin to feel pains throughout his body. His doctors would do tests, detect nothing, and reassure him that he still seemed clear.  In early November 2010, he was in pain, stopped eating and had to be fed intravenously by a nurse who came to his house. The doctors found no sign of more tumours, and they assumed that this was just another of his periodic cycles of fighting infections and digestive maladies.

Heres’ a great bunch of TV interviews (something Jobs didn’t do very often).  “The last few years have reminded me that life is fragile”.  Click here (worth watching the whole 10 minutes). His final TV appearance was in June 2011 to the Cupertino City Council about the acquisition of land for their new campus.  Worth watching some of it: Click here.

The End

In early 2011, doctors detected the recurrence that was causing these symptoms. Ultimately, he developed liver, bone, and other metastases.  He had a further extended leave of absence from his job before stepping down as Apple CEO in Aug,  Steve Jobs eventually died 5 Oct 2011.

steve jobs 2010
The last few years have reminded me that life is fragile

References

Notwithstanding the Pancreatic Cancer vs Neuroendocrine Cancer issue, I carried out my research mainly using two articles of the many you can find out there:

  1.  “And one more thing” about Steve Jobs’ battle with cancer
    This is a long article and totally fascinating.  Some of the evidence is presented using extracts from Walter Isaacson’s book ‘Steve Jobs’
  2. A Tumor Is No Clearer in Hindsight.  This article comes to similar conclusions than the one above but it’s shorter and easier to read. It’s from the New York times and was written after the dust settled on Jobs’ death (i.e. when more facts were available). There is also input to this article from NET specialists Dr Wolin and Dr Libutti.

  3. Apple chief Steve Jobs: Health timeline since 2003.  This article is from a UK National Newspaper (The Telegraph) but via US Business Publication Bloomberg.

Personal Summary

“A tumor is no clearer in hindsight” is a good summary on the basis that I would have liked much more detail!  During my research, I found many mentions of Insulin as stated above but only one or two mentioning Glucagon, a hormone associated with another pNET type – Glucagonoma. However, looking at this tumor type in the ISI Book (Woltering et al) and the Jobs diagnostic and treatment story, I have some doubts whether this was the precise tumor type. I have some other searches in progress hoping to find something concrete.

Thinking Differently There is no doubt that Steve Jobs was an amazing and very interesting character.  You just can’t see Apple being the Apple it is today without his intervention.  He was famous for being ‘unconventional’ and ‘thinking different’ and I get that element of his character.  I just can’t help thinking that perhaps he should have been more ‘conventional’ with this thinking and approach to treating his cancer. However, we just don’t know what advice he was receiving and what advice he accepted or rejected.  As for the ‘Pancreatic Cancer’ thing – I’ve said this before, I believe patients only say or interpret what their doctors say to them in regards cancer type.

“The most famous patient ambassador we never had”.  I don’t mean any disrespect by that, I’m just emphasising that we need so much more awareness of our cancer and a high-profile patient could do so much to help in this area. If he was so inclined, Steve would have been a fantastic advocate for Neuroendocrine Cancer and there’s an area where perhaps thinking different might be the way ahead. However, I have a suspicion that very famous people don’t really want to talk about their illness and Steve Jobs might even perceive that as a weakness.

And one more thing …….  you may also find this article useful.  It’s titled “And one more thing”

 

Neuroendocrine Cancer – tumour markers and hormone levels


blood tests

I think most people have had a form of medical testing at some point in their life, i.e. the sampling and testing of blood, urine, saliva, stool or body tissue. In a nutshell, the medical staff are just measuring the content of a ‘substance’ and then taking a view whether this is normal or not based on pre-determined ranges. These tests are normally done as a physician’s reaction to symptom presentation or maintenance/surveillance of an existing diagnosed condition. Sometimes, abnormal results will lead to more specialist tests.

In cancer, these tests are frequently called ‘markers’. Most tumour markers are made by normal cells as well as by cancer cells; however, they are produced at much higher levels in cancerous conditions. These substances can be found in the blood, urine, stool, tumour tissue, or other tissues or bodily fluids of some patients with cancer. Most tumour markers are proteins. However, more recently, patterns of gene expression and changes to DNA have also begun to be used as tumour markers.  Many different tumour markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with two or more cancer types. No “universal” tumour marker that can detect any type of cancer has been found.

markers

There are some limitations to the use of tumor markers. Sometimes, noncancerous conditions can cause the levels of certain tumor markers to increase. In addition, not everyone with a particular type of cancer will have a higher level of a tumour marker associated with that cancer. Moreover, tumour markers have not been identified for every type of cancer. Tumour markers are not foolproof and other tests and checks are usually needed to learn more about a possible cancer or recurrence.

I’d also like to talk about a group of associated tests, in particular, hormone levels as these tests are really important to help determine the type of Neuroendocrine Tumour.  NETs will sometimes oversecrete hormones and this can give clues to the type.  The constraints mentioned above apply to hormone levels and other tests to a certain extent.

What this article will not cover

Routine Testing – the post will not cover routine blood tests (i.e. complete blood count etc).  Although they may point to a problem, these tests do not necessarily indicate a particular type of NET without other supporting evidence.

Biopsy Testing – Technically, the Immunohistochemical ‘stains’ used in biopsy testing are tumour markers but I’ll not be discussing that today. I did cover the output of biopsies in my blog on NETs – Stages and Grades.

Genetic Testing.  This is very specialised but you may find my Genetics and NETs article is of interest.

Sequencing of marker testing – diagnosis

The sequencing of marker testing may have been different for many patients.  In my own experience, I had a biopsy and then the biochemical checks were carried out. So regardless of the results of my marker tests, I was to be diagnosed with NETs. Those with lengthy and difficult diagnostic phases will perhaps have had a different sequence with the biochemical markers providing evidence for further tests to formally diagnose.  Markers alone will normally not be enough for a diagnosis but they do, however, feed into the treatment plan and provide a baseline at diagnosis and for tracking going forward.

Interpreting test results – International/National/Regional differences

The use of markers tends to be different on an international basis, e.g. specific marker tests can be developed in-country by independent labs. Testing can also vary in the same country as in-country labs use different commercially available ‘testing kits’. Not all tests are available in all countries.

Reference ranges can be dependent on many factors, including patient age, gender, sample population, and test method, and numeric test results can have different meanings in different laboratories. The lab report containing your test results should include the relevant reference range for your test(s). Please consult your doctor or the laboratory that performed the tests to obtain the reference range if you do not have the lab report. Moreover, the ‘normal’ test range can vary from hospital to hospital, even within the same tests. I suspect clinical staff have their own versions of risk thresholds when dealing with test results. Even when results are just above or below, individual physicians can take their own view in a subjective manner. Testing is best done at the same lab each time if possible.

There’s a great website called LabTestsOnline which can describe each test. It’s peer-reviewed, non-commercial and patient-focused but just please note you should always refer to your own lab ‘normal ranges’ which will be printed on your test results.  For these reasons, you will not find reference ranges for the majority of tests described on this web site.  The link above will take you to the list of ‘country’ affiliated versions with specific information on a country basis.

Here’s some tips I always give people:

1 – Always try to get your own copy of results (preferably on paper) and track them yourself (I use a spreadsheet).

2 – When comparing results inside patient forums, always add the range and if possible, the unit of measurement (i.e. g/L, mmol/L, umol/L etc etc).  Failure to do this can at best confuse, and at worst frighten patients.  Compare apples with apples not with pears! (this is why it’s important to know the unit of measure and the reference range in addition to the figure).

3 – Don’t get too excited about rises if the test is still inside the normal range – normal is normal!

4 – Don’t get too excited about rises taking you just outside of normal range – your doctors are looking for bigger spikes.

5. Don’t get too excited about a single test result, your doctors are looking for trends, a single test result is not much to go on.

NET Markers

Although some routine blood markers (complete blood count etc) are useful in NETs, it’s pretty much impossible to cover these in any general detail.  I’m going to focus on tumor and hormone associated markers

There are many markers involved with NETs. Some do different jobs and some are just variants measuring the same thing (more or less efficiently). You may also see something called ‘gold standard’ in reference to NET Tumour markers. Although thinking is changing (more on this below) and can vary from country to country, it is generally accepted that Chromogranin A and 5HIAA are the gold standard markers for tumour bulk and tumour functionality respectively.  These gold standard tests may not be applicable to every type of NET, particularly 5HIAA. I’m also aware that US doctors are reducing the dependency on CgA and using Pancreastatin instead (although many are measuring both).

NETs are known to be heterogeneous in nature (i.e. consisting of or composed of dissimilar elements; not having a uniform quality throughout).  Whilst some markers can be used widely, it follows that there are many very specialist marker tests for individual types of NET.  I think this applies to 3 broad categories of NETs: Tumours known to potentially oversecrete Serotonin and and perhaps others (mainly midgut), Pancreatic NETs (or pNETs) secreting various hormones by type; and other less common types and/or syndromes which might be considered by some to be even more complex than the former two and in some cases there are big overlaps.

Another interesting thing about NET markers is that an undiagnosed patient may undergo several specialist tests to eliminate the many possibilities that are being presented as vague and common symptoms.  Sometimes this is necessary to eliminate or ‘home in’ on a tumour type or syndrome/hormone involved (it’s that jigsaw thing again!).

Markers too can be divided into broad categories, those measuring how much tumour is in your body and its growth potential and those measuring how functional (or not) those tumours are.  The latter can probably be expanded to measure/assess excess hormone secretion and syndromes.

The Anatomy

Certain tests can be anatomy related so to add context and to prevent big repetitive lists when using the terms ‘foregut’, ‘midgut’ and ‘hindgut’, you may find this graphic useful.

foregut midgut hindgut

Markers for measuring Tumour bulk or load/growth prediction

Chromogranin (plasma/blood test)

cgaChromogranin is an acidic protein released along with catecholamines from chromaffin cells and nerve terminals. This statement alone might explain why it is a good marker to use with NETs.  Depending on the test kit being used, you may see test results for Chromogranin A (CgA) and Chromogranin B (CgB) – the inclusion of CgB tends to be confined to Europe. There is also mention of Chromogranin C (CgC) in places but I’ve never heard of this being used in conjunction with NETs.

One of the disadvantages of CgA is that the results can be skewed by those taking Proton Pump Inhibitors (PPIs).  Many NET patients are taking PPIs to treat GERD (….and Zollinger-Ellison Syndrome). In the long-term, this has the result of increasing gastrin levels which can lead to an increase of CgA in the blood including for some months after discontinuing.  Opinions differ but many texts I found did suggest stopping PPIs for 2 weeks before the CgA blood test.  CgB is said not be as influenced by the use of PPI as CgA. In addition to the issue with PPIs, CgA levels may also be elevated in other illnesses including severe hypertension and renal insufficiency. CgB is also said to be more sensitive to Pheochromocytoma.

Elevated CgA is a constant and somewhat excitable discussion point on patient forums and not just because of the lack of unit of measurement use I discussed above. Some people get quite excited about a single test result.  I refer to Dr Woltering et al (ISI Book) where it clearly states that changes in CgA levels of more than 25% over baseline are considered significant and a trend in serial CgA levels over time has been proven to be a useful predictor of tumour growth (i.e. a single test result with an insignificant rise may not be important on its own).  Dr Woltering also gives good advice on marker tests when he says “normal is normal” (i.e. an increased result which is still in range is normal).

Here is a nice graphic explaining what else could be the cause of elevated CgA:

causes-of-cga-elevated

CgA appears to be a widely used tumour marker and is effective in most NETs (foregut, midgut and hindgut). It is also sensitive to Pheochromocytoma, particularly when correlated with a 131I-MIBG scan. Interestingly Chromogranin can also be used in the immunohistochemical staining of NET biopsy samples (along with other methods).

As for my own experience, my CgA was only elevated at diagnosis, remained elevated after intestinal surgery but returned to normal after liver surgery (indicating the effect of liver tumour bulk on results).  It also spiked out of range when some growth in a distant left axillary node was reported in Jan 2012.  Following a lymphadenectomy, it returned to normal again and has remained in range to this day.  It has been a good predictor of tumour bulk for me and I’m currently tested every 6 months.

Pancreastatin

In effect, this marker does the same job as CgA.  Interestingly, Pancreastatin is actually a fragment of the CgA molecule. There have been many studies (mainly in the US) indicating this is a more efficient marker than CgA, and not only because it is not influenced by the use of PPI.  It has also been suggested that it’s more sensitive than CgA and therefore capable of detecting early increases in tumour burden. It has also been suggested it can be an indication of tumour ‘activity’ (whatever that means). It is widely used in the US and some physicians will use it in preference to CgA (…..although from what I read, CgA also seems to be tested alongside).  I’m starting to see this mentioned in the UK.

Neurokinin A (NKA)

This is not a well publicised test. However, it is something used in USA but I’d like to hear from others to validate its use elsewhere.  In a nutshell, this test, which only applies to well differentiated midgut NETs, appears to have some prognostic indication.  I discovered this test in the ISI NET Guidance and it’s backed up by a study authored by names such as Woltering, O’Dorisio, Vinik, et al.  This is not a one-off test but one designed to be taken serially, i.e. a number of consecutive tests.  These authors believe that NKA can also aid in the early identification of patients with more aggressive tumors, allowing for better clinical management of these patients.  NKA is sometimes called Substance K.

Neuron-Specific Enolase (NSE)

In patients with suspected NET who have no clear elevations in the primary tumor markers used to diagnose these conditions, an elevated serum NSE level supports the clinical suspicion.

Markers for measuring Tumour functionality/hormone/peptide levels

So far, I’ve covered basic tumor markers which have a tumor bulk and/or prognostic indication.  This section is a slightly more complex area and many more tests are involved. There’s often a correlation between CgA/Pancreastatin and these type of markers in many patients i.e. a serial high level of CgA might indicate a high level of tumour bulk and therefore increased production of a hormone in patients with a syndrome or oversecreting tumor. However, it frequently does not work out like that, particularly when dealing with non-functioning tumours.

The type of marker for this element of NET diagnosis and surveillance will vary depending on the type of NET and its location (to a certain extent).  Like tumour bulk/growth, there might be different options or test variants on an international basis. There are too many to list here, so I’ll only cover the most common.

Serotonin Secreting Tumors

There are a few markers in use for measuring the functionality of this grouping of tumours. This tumour group has a tendency to secrete excess amounts of the hormone Serotonin although it differs depending on the area of the primary. For example, hindgut tumours tend to secret lower levels than foregut and midgut and therefore this test may present within range.  Please also note there may be other hormones of note involved. The antiquated and misleading term ‘Carcinoid’ is sometimes used as a descriptor for these tumours and more and more NET scientific organisations and specialists are now avoiding use of this term.

lug-the-jug
Lug the Jug

5HIAA.  5HIAA is a metabolite of Serotonin thus why it’s a useful thing to measure to assess functionality in this grouping of tumours. 5HIAA is actually the ‘gold standard’ test for functioning serotonin secreting tumours. It’s a key measure of the effects of carcinoid syndrome and the risk of succumbing to carcinoid heart disease.  However, there are two methods of testing:  Urine and Plasma.  The rather obvious key difference between the two is practicality. With the 24 hour urine, there are two key issues: 1.  The logistics (i.e. lug the jug).  2. Fasting for up to 3 days prior to the test (4 if you count the day of the test). There are numerous variations on the fasting theme but most labs tend to say not to eat at least the following foods that contain high levels of serotonin producing amines: avocados, bananas, chocolate, kiwi fruit, pineapple, plums, tomatoes, and walnuts.  Some lists contain additional items. With the plasma version, the fasting period is reduced to 8 hours (although I’ve seen some labs increase that to 10 or 12). There are also medicinal limitations including drugs that can also alter 5-HIAA urine values, such as acetanilide, phenacetin, glyceryl guaiacolate (found in many cough syrups), methocarbamol, and reserpine. Drugs that can decrease urinary 5-HIAA levels include heparin, isoniazid, levodopa, monoamine oxidase inhibitors, methenamine, methyldopa, phenothiazines, and tricyclic antidepressants. Patients should talk to their doctor before decreasing or discontinuing any medications. Taking 5HTP supplements are possibly not advised either prior to the test either.

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

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

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

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

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

Gastric NETs (Stomach)

Testing will be different depending on the Type:

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

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

NETs of the Pancreas (pNETs)

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

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

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

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

Notes:

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

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

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

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

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

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

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

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

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

Insulinoma – Insulin, Proinsulin, C-peptide

Gastrinoma– Gastrin, Gastrin pH

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

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

Somatostatinoma – Somatostatin (plasma somatostatin like immunoreactivity)

PPoma – Pancreatic Polypeptide (PP)

Other NETs/Syndromes

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

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

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

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

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

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

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

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

Cortisol

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

Other hormones related to ACC include:

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

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

Aldosterone – weight gain, high blood pressure.

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

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

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

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

The Future – Molecular Markers?

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

Tumour Markers and Hormone levels – complex subject!

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Surgery for NETs – Chop Chop

Carcinoid liver tumour debulking
Liver tumour debulking

At the end of 2014, I was feeling pretty good celebrating 4 years since my first ‘big’ surgery in 2010. It prompted me to write an article Surgery – the gift that keeps on giving. In that particlar article, I really just wanted to say I was grateful for the early surgical treatment and as I was just about to spend another Christmas with my family, I was reminiscing what a wonderful gift it was at the time. Other than some detail of the surgery, I didn’t get too technical, I just wanted to generate a thankful and festive mood. However, a recent private message from a subscriber prompted me to study the current benefits of surgery for Neuroendocrine Tumours (NETs) in more detail just to ensure my understanding was still in line with best practice.

It’s very well known that NETs can present a major challenge to physicians in their recognition and treatment requirements.  For example, NETs can cause various syndromes, not only for requiring treatment for primary and loco-regional tumours to minimise the risk of abdominal complications and future growth; but also for removal of tumour including liver and other metastases to palliate hormonal symptoms. Some tumours can be quite large and require extensive surgery to remove.

I searched reputable websites and European and North American NET treatment guidelines to find that surgical treatment of these tumours still appears to remain an important intervention, not just for curative treatment (where this is possible) but also for symptom palliation and survival. Although more treatment modalities are available than ever before (e.g. radiotherapy including PRRT, liver embolisation, liver ablation, somatostatin analogues and other new drugs, some with chemo combinations), surgery still appears to be the mainstay treatment to be offered when it is appropriate.  For some it isn’t appropriate or will be held in reserve for watch and wait scenarios or as ‘adjuvant’ treatment downstream. On paper, it appears to be the only current option for a curative scenario if the cancer is caught early enough.

I had an amazing surgeon with an impressive CV in Neuroendocrine disease.  He believes in early and aggressive surgery (within normal guidelines) and always in conjunction with other treatment modalities and only when required.  I found a video of one of his lectures which you may find useful.  Another surgeon who talks with knowledge and passion is Dr Pommier and one of his videos can be viewed here. I’m sure there are many others.   They are different characters but they both seem to believe in getting as much tumour out as early as possible and also emphasise that sometimes it can be too risky so the focus moves to other treatment.  Both presentations provide statistical evidence that debulking/cytoreductive surgery can often offer a better outlook even for those with advanced neuroendocrine disease.

I think I have a soft spot for surgeons – they also seem to love their job despite it being particularly ‘gory’.  On the subject of ‘gory’, I recently came across another surgical video which I found totally fascinating.  This one contains amazing footage of real surgery and if you are like me, you will find this very educational. It’s also fairly recent (2014) so perhaps offers more up to date techniques. It’s also a very well structured presentation. Some of you may have seen it before and some of you could even have even been at the presentation! If you don’t have time, skip forward to approximately ’19 minutes’ and watch them take out large and small tumours of the liver using a technique called enucleation!   (Click here to watch).

Hope you enjoyed this session as much as I enjoyed writing it!

Thanks for listening

Thanks for reading

Ronny

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