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Neuroendocrine Tumours – Grade and Stage (incorporating WHO 2017 changes)


One of the most discussed and sometimes confusing subjects on forums is the staging and grading of Neuroendocrine Neoplasms (NENs). Mixing them up is a common error and so it’s important to understand the difference despite the apparent complexity. If I was to make a list of questions for my specialist/Oncologist at diagnosis, it would include “What is the stage and grade of my cancer”.  To enable me to synchronise with the documented guidance, I’m going to use the following terms in this post:

Neuroendocrine Neoplasm (NEN) – all types of Neuroendocrine tumour of whatever grade (Neoplasm is another word for tumour and a tumour can be benign or malignant)

Neuroendocrine Tumour (NET) – all well-differentiated tumours (an explanation of differentiation will be provided below)

Neuroencirone Carcinoma (NEC) – all poorly differentiated tumours

In the most basic of terms, stage is the spread of cancer and grade is the aggressiveness of cancer. They are totally different things and an understanding is important as they are both critical to predict outcome (to a certain extent) and guide therapy. There is no correlation between the two, you can have the lowest grade with the highest stage (common in NETs). I’m also including information on something known as ‘differentiation’ as this is also a key point for NETs grading.

As patients, we deal with many medical specialists during diagnosis and subsequent treatment.  However, we rarely meet the pathologist who plays a critical role in the outcome. Precise diagnosis is what drives patient decisions and treatment. If the pathology is wrong, everything that follows could be incorrect as well.  It’s a very important area.

Grading (aggressiveness)

To fully understand grading, you also need to understand the concept of ‘differentiation’.  In the most basic of terms, ‘differentiation’ refers to the extent to which the cancerous cells resemble their non-cancerous counterparts.  This is an important point for NETs because many low-grade tumour cells can look very similar to normal cells. Tumours fall into one of three grades based on their differentiation and their proliferative rate. The proliferative rate is measured mainly using two methods known as Miotic Count and Ki-67 index, the latter seems to be more frequently used. The Ki-67 index can usually be determined, even in cases of small biopsies but Mitotic rate counting requires a moderate amount of tumour tissue (at least 50 HPFs or 10 mm) and may not be feasible for small biopsies.  The Miotic Count method may be preferred or used in addition to Ki-67 for certain Lung NET scenarios as it is said to be more helpful in distinguishing atypical from typical NET (Carcinoid tumours), and for small and large cell lung Neuroendocrine Carcinomas (NEC). Some of you may have heard the term ‘moderately differentiated’ which tended to align with an intermediate grade or Grade 2. However, please note that the term moderately differentiated as a classification was phased out in 2010 by WHO reducing from 3 levels to 2.  Grade 2 is also defined as well differentiated but based on different proliferative rate (see table). High grade is normally referred to as Neuroendocrine Carcinoma indicating it is a faster growing and more aggressive cancer.

WHO 2017 changes

The 2017 World Health Organisation (WHO) classification sub-divided Grade 3 into two new entities: 3a – a well differentiated high-grade and 3b – a poorly differentiated high-grade NEC.  There may also be a cut-off point in proliferative rate (i,e, Ki-67) between NET and NEC (including different cut-offs for different types but this is not yet clear.  The grade Ki-67 cut-off is changed from 2 to

It also introduced a change to the naming of mixed cell tumours from Mixed AdenoNeuroendocrine Carcinoma (MANEC) to Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).  A full explanation of this MiNEN will follow but I would suggest the use of the term ‘Neoplasm’ rather than ‘Carcinoma’ is an indication that these tumours are not automatically classified as Grade 3/High Grade.  

Misc Grading Issues

The proliferative rate can be diverse in NENs, so sampling issues can limit the accuracy of grading. More substantial samples of tumour are therefore preferable for grading thus why the Ki-67 index is preferred for biopsies where large amounts of tissue may not be available. The distinction of low-grade from intermediate grade can be challenging when using small samples. A couple of interesting observations about NET grading which I spotted during my research and ‘forum watching’.  You can have multiple primary tumours and these might have different Ki-67 scores.  Additionally, on larger tumours, Ki-67 scores can be different on different parts of the tumour.  And something I know from my own experience, secondary tumours can have different Ki-67 scores than primary – even a different grade.  In my own case, my liver secondary tumours were graded higher than my primary which according to my surgeon is in keeping with a clone of the disease having become more aggressive over time.  Royal Free Hospital NET Centre indicates a person’s grade should be taken from the highest biopsy grade taken.  This is a fairly complex area but a recent study published by the US National Institute of Health and many anecdotal comments made by NET specialists indicates that is a fairly common scenario.

Staging (spread)

Staging is the extent or spread of disease.  Most types of cancer have 4 stages, numbered from 1 to 4. Often doctors write the stage down in Roman numerals. So you may see stage 4 written down as stage IV.  In addition to this standard method, there is also an agreed model known as TNM (Primary Tumour, Regional Node, Distant Metastasis) which is essentially a more detailed staging definition when combined with the Stage 1-4 model.  Please note with TNM models, there could be different stage descriptions depending on the location of the primary tumour and similarly different TNM models for different tumour locations.

WHO 2017 changes

WHO 2017 has recommended enhancements to the TNM system mainly the use of additional suffixes indicating the extent of lymph node involvement. Details to follow.

The following example shows the stage descriptions for a NET of the small intestine (the others are similar but worded accordingly for that part of the anatomy):

Stage 1 tumour is less than 1 cm in size and has not spread to the lymph nodes or other parts of the body

Stage 2 tumour is greater than 1 cm in size and has started to spread beyond the original location, but has not spread to the lymph nodes or other parts of the body

Stage 3 is any size tumour that has spread to nearby areas of the body and also to at least one lymph node.

Stage 4 is any size tumour that has spread to one or more lymph nodes and has also spread to other, more distant areas of the body (such as the liver).

It’s also worth pointing out that Stage 4 does not necessarily mean a cancer is more dangerous than other cancers of lesser stages.  This is an important point for most NETs where Stage 4 can be apparent with a low-grade tumour i.e. Stage 4 for lower grade NETs is very often not the ‘red flag’ it is for other more aggressive cancers.  For example, doctors may surgically remove a Stage 4 NET, while surgery might not help a patient with different cancer at such a late stage.

Notes:

  • Sometimes doctors use the letters to further divide the number categories – for example, stage 2A or stage 3B.  This is normally to clarify or provide more detail of the primary tumour size/invasion in conjunction with the TNM model.
  • You may also see something called Stage 0 which is for ‘Carcinoma in situ’. It means that there is a group of abnormal cells in an area of the body. However, the number of abnormal cells is too small to form a tumour and may, therefore, be currently classed as benign.  The World Health Organisation (WHO) system does not appear to recognise Stage 0 for NETs.

The most generic model for TNM staging is below but please note this could be adjusted for particular types of NET.

Primary Tumor (T)
TX: Primary tumor cannot be evaluated
T0: No evidence of primary tumour
Tis: in situ (abnormal cells are present but have not spread to neighbouring tissue; although not cancer, in situ may become cancer and is sometimes called preinvasive cancer)

T1, T2, T3 and T4 is a measure of the size of, and/or invasion/penetration by, the primary tumour and the wording varies between different NET sites. e.g. for a small intestinal NET:

T1 tumour invades mucosa or submucosa and size <=1 cm

T2 tumour invades muscularis propria or size >1 cm

T3 tumour invades subserosa

T4 tumour invades the visceral peritoneum (serosa)/other organs

For any T add (m) for multiple tumours

Regional Lymph Nodes (N)
NX: Regional lymph nodes cannot be evaluated
N0: No regional lymph node involvement
N1: regional lymph node metastasis

Distant Metastasis (M)
MX: Distant metastasis cannot be evaluated
M0: No distant metastasis
M1: Distant metastasis is present

You may occasionally see TNM staging be prefixed by lower case letters.  The most commonly used prefix is ‘p’ simply meaning the grading has been confirmed by pathology.  e.g. pT4 N1 M1

Specialists can combine the Stage to create a TNM – for example:

Summary

A complex area and I hope I have condensed it sufficiently for you to understand enough for your purposes.  Despite looking very scientific, it is not an exact science. There are many variables as there always are with a Neuroendocrine disease.  NENs can be very challenging for a pathologist even an experienced one who may not have encountered NENs before.  However, it is an extremely important part of initial diagnosis and also when needed during surveillance.  It is a vital tool used by Multidisciplinary Teams (MDT) in treatment plans and for prognostic purposes.  If you need to learn further, I recommend this document:

ESMO Annals of Oncology – Clinical Guidelines for Neuroendocrine gastro-entero-pancreatic tumours (bearing in mind this will not have been updated as per above – other than that it is useful).

If you are interested in this subject and have one hour to spare, there is a great video here from LACNETS worth watching.  <>Finally – always make sure you get your pathology results at diagnosis and following any subsequent sampling.

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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Your Money or Your Life


Danielle

“old enough to know better but young enough not to die of cancer”

I first wrote about Danielle Tindle in Nov 2015 as I was really inspired by her story. The inspiration came with a message of hope. Some of you will know that I have a lot of time for inspiring patient stories such as this one also knowing that I believe these should be at the forefront of international and national campaigns.

I just published a new blog entitled simply …. I CAN.   Danielle Tindle is one example of someone who can.  A young person who had gone through grueling treatment (several chemos and stem cell treatment) to get rid of Hodgkin’s Lymphoma and just when she thought her life was back and near the end of a PhD, they found a Neuroendocrine Tumour in her neck near the larynx which was inoperable and chemo was found to be ineffective. Despite this, she battles on.  Her father, a scientist, researched an experimental immunotherapy drug currently being used for Melanoma.  Danielle has confirmed to me that she was previously on Keytruda – Pembrozilumab (the Jimmy Carter drug) but she is now having a combination of Nivolumab and Ipilumumab.

Down the line, Danielle has now appeared on National TV in Australia.  In addition to Danielle’s own quest, this is clearly good exposure for Neuroendocrine Cancer and for me it was like Part 2 of the video story which I have retained in this blog near the end (worth watching before the National TV programme).

It also highlighted a growing problem which appears to be causing concern in many countries and that is the price of drugs compounded by health system processes. How crazy is this …….  the drug Danielle wants to take on an experimental basis (it is not approved for Neuroendocrine Cancers) would only cost AUS$6 AUS if she was a Melanoma patient but because she has Neuroendocrine Cancer, it is costing AUS$5000 a shot for the treatment she needs.  This would appear to be the last chance treatment for Danielle so it is really a case of your money or your life.

You can view the 30-minute ABC ‘Australian Story’ by clicking here

When I wrote the original blog, I attached a 5-minute video which I personally found very inspiring.  She talks eloquently, confidently and she maintains her composure emotionally with only small signs of losing it which is perfectly understandable.  She is a brave lady and I’m not sure I could have contained my emotions for the full 5 minutes of the video clip. You can view the video clip here: Click here to view

Good luck Danielle, I’m really hoping you can resolve the funding for this treatment and I really hope it works out.  You are a very brave and inspiring lady.

Thanks for listening

Ronny

(Please also note this post is not an endorsement of any fundraising that may be associated with the videos)

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Scanxiety – I just don’t get it!


'Scanxiety' - I just don't get it

‘Scanxiety’ – I just don’t get it

The internet is full of blogs and articles about a subject which is described as ‘scanxiety’ – the joining of the words ‘scan’ and ‘anxiety’. I also noted some authors using the words ‘scanxiety’ and ‘anxiety’ interchangeably which in my opinion is clearly wrong.

‘Scanxiety’  – I just don’t get it  ……or more accurately I just don’t get overly anxious about scans. Why? Because testing (scans in particular) is the one thing that’s going to keep me alive for as long as possible.  I was diagnosed 5 years ago thanks to the trigger of precautionary tests including a scan. I now live with the knowledge (and I accept this fact) that there are still bits of cancer inside me.  If I am not regularly tested, there is a chance I will eventually succumb to a serious or irreversible problem which should have been spotted earlier. Even in the event of ‘not so good news’ following a routine surveillance scan, I still see that as a positive because it means the testing has worked and an investigation can be commenced to more accurately localise and treat the problem. Even if you are in the diagnostic phase and a scan is ordered, you need to get right inside that machine and get it over and done with.  It just might save your life.

Users of the phrase also extend its meaning to waiting on the results of the scan.  I also find this odd as scanning is just one test and just one test result. Thinking back to my own countless appointments either for testing, treatment or for receiving results, I appear to be consistently pragmatic in my approach – the test results will be what the test results will be and I will save any worry until I know if I have anything to worry about.

Many cancer patients are under surveillance for a long time and are tested regularly. As an incurable cancer patient myself, I sometimes feel like I’m in a perpetual state of testing. I suspect if I was to let anxiety get the better of me, that would simply lead to other complications I just don’t need.  I’m not that insensitive to forget that some people do probably get anxious about actually climbing into a scanner, particularly if they are claustrophobic but that is already a recognised anxiety issue rather than so-called scanxiety.  I also suspect people will be anxious about their relatives having scans, particularly the first diagnostic one, worse when young ones are involved and I totally get that. Anxiety (as opposed to so called scanxiety) is a pretty natural reaction.  However, to control your fears, you need to face them and then try not to let your anxiety filter down to others.

Scanxiety – I just don’t get it.  As for the 20,300 search results on the internet, I just don’t get that either!

Thanks for listening

Ronny

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Not all Cancer is simple


Not all Cancer is simple

Not all Cancer is simple

So Victoria Derbyshire has breast cancer and has used her ‘workplace’ as a platform to let people know she is a determined survivor. Nothing wrong with that, it’s great cancer awareness for some and inspiration for others (including me). However, reading through various newspaper follow-up articles, blogs and social media comments, I can see criticism by many for producing an over simplified message (see picture below).  Although many of us will be wishing it was so, not all cancer is simple!

victoriaTake Neuroendocrine Cancer for example. For some, this ‘silent’ cancer can take years to be finally diagnosed whilst the patient is misdiagnosed with other conditions often with debilitating symptoms. Once diagnosed, surgery (if it’s possible) is just one of a number of treatment options and it will often be multiple times.  Follow on treatments include an array of biochemical and nuclear options. If the disease is metastatic, which it frequently is due to its years of ‘silence’, then the condition normally becomes incurable and the patient will be treated for the forseeable future, very often with a reduced quality of life. Victoria might not think she had a fight but for many others, this is a particularly apt word – especially those who can never be sure the cancer has gone.

I’m not suggesting that well-known people shouldn’t make their cancer experience public – in fact I’m all for that!

Get well soon Victoria, I really mean that.

Cancer? it’s what other people get


Other people get Cancer but not me

Other people get Cancer but not me

My recent hospital visit brought back some memories as I walked past the Acute Admissions Ward.  I thought back to my emergency weekend stay there in July 2010. I’ve blogged about my diagnosis before but not about this ‘incident’ which occurred almost immediately prior.

I was well into the ‘diagnostic phase’, having had all sorts of tests including a liver biopsy.  I vividly remember thinking these tests were a ‘nuisance’, I was far too busy and I didn’t even feel ill.  In hindsight, I was fortunate to have had such a thorough bunch of physicians who diagnosed me with metastatic Neuroendocrine Cancer in about 6 weeks ‘flash to bang’.  I intentionally just used a phrase associated with ‘quick’ because in the world of Neuroendocrine Cancer, 6 weeks is ‘warp speed’.

So why was I admitted to hospital during the diagnostic phase?  Because I was stupid.  In fact I was double-stupid.  Firstly, despite having had to undergo a liver biopsy and a referral to an Oncologist, I was in a dismissive frame of mind and was blanking out any thought that I actually had cancer.  I didn’t have time for it, I was far too busy.  I’m in control!  Secondly, despite being told to take it easy after the liver biopsy, I ignored that advice because I was far too busy getting on with a normal life. After all, this is just another test hurdle and I’ll get the all clear. Other people get Cancer but not me.

On the weekend following the liver biopsy, the family came round, so I decided to do normal things like lifting one of my grandsons up and swinging him around my head (as one does) and I prepared the BBQ which involved lifting a 13.5kg cannister of gas from the garage onto the patio.  Why not? I didn’t have anything wrong with me and I didn’t even feel ill….. the doctors were just being cautious.

However, as that Saturday afternoon progressed so did the pain; and to the point that I knew I had to seek help. To cut a long story short, I was eventually admitted to hospital for what was to be diagnosed as a bleed on my liver at the biopsy site.  Oh how the mighty fall.

On the positive side, I got another bunch of tests including scans as confirmation (….a second opinion from a different hospital).  However, it was the wake-up call I needed to take it seriously. I was discharged on the Monday in time for my very first Oncology appointment with my wife Chris in attendance.  For the first time, we were officially told I had Cancer – it was much more than just a ‘scare’.  For me, the denial was over, indicating that I was never actually in control of what was happening to me.

Finally some food for thought …… In hindsight, I made the serious mistake of not talking to anyone about my denial and I suspect that led to me acting stupidly.

It really is OK to talk about Cancer

Ronny
p.s. I’m now slightly mellower about Cancer 🙂 You might say I’m back in control?

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I bet my flush beats yours?


royal_flush_w

There are different types of flush!

Neuroendocrine Cancers can sometimes present with one or more vague symptoms which occasionally results in a lengthy diagnostic phase for some.  Sure, there can be issues with doctor experience and knowledge that can add to the problem. However, some people do present with multiple vague and confusing symptoms and some people have comorbidities which have similar symptoms.  Textbook diagnostics just don’t make sense, sometimes even when the doctor suspects Neuroendocrine Cancer i.e. classic symptoms of ‘something’ but with negative markers for NETs. Clearly those are extreme cases and just like other complex diseases, many diagnoses of Neuroendocrine Cancer can be extremely challenging.  Even for an experienced doctor, it can be a difficult jigsaw!

Most types of Neuroendocrine Cancer can be accompanied by a ‘syndrome’ i.e. the tumours are ‘functional’ and this is normally (but not always) associated with metastatic disease. At this point it’s also worthwhile saying that some Neuroendocrine Cancers can be ‘silent’ (non-functional) for years before any symptoms show and it’s only when they metastasize, that these clinical syndromes come to life. Ironically, the manifestation of the disease with a syndrome can occasionally turn out to be a life saver albeit the cancer is normally incurable at this stage – but still treatable.

The most common Neuroendocrine Cancer is (currently) known as Carcinoid (>50%).  It can present as a collection of symptoms known as Carcinoid Syndrome and the most common one is flushing with approximately 84% frequency.  Others symptoms include (but are not limited to) diarrhoea, heart palpitations, stomach cramps and general abdominal pain/discomfort, shortness of breath, wheezing.  You can see the scope for confusion and misdiagnosis.  You may find my blog on the ‘5 E’s of Carcinoid Syndrome’ useful.

When you look at these general Carcinoid Syndrome symptoms, flushing seems to be the one that stands out as a ‘cardinal sign’ whereas many others are vague and easily confused with common/regular illnesses.  However, the flushing is reported to be different from most people’s perceptions of a ‘flush’.  The Carcinoid flush is almost always ‘dry’.  To quote my ‘amazing yellow book‘ (co-authored by Dr Gene Woltering), “…. a good rule of thumb is if the flushing is wet (accompanied by sweating), it is due to a cause other than Carcinoid”.   Dr James Yao, another well known NETs guru also raises this distinction by stating…. “The facial flushing of carcinoid syndrome is usually a dry flushing, and not associated with sweating like other kinds of flushing. The flushing is often a symptom that others notice before patients do. They may not feel it themselves.”

Additionally, there appears to be at least two varieties of flushing in Carcinoid Syndrome related to two different anatomical regions of the primary tumour (again a useful guide from my amazing yellow book):

1.  Midgut (generally the small intestines (less the duodenal 1st portion), ascending colon, appendix) – faint pink to red in colour, involved face and upper trunk, normally lasts a few minutes and can occur many times per day.

2. Foregut (generally the stomach, lung, thymic and duodenal 1st portion) – more intense, longer duration, purplish, upper trunk and occasionally limbs.

The flushing sympton has many potential triggers and can be attributed to the secretion of excess hormones associated with Neuroendocrine Tumours. Although many people focus on serotonin as the main culprit, there is significant evidence to suggest that other hormones may be playing a bigger part with this symptom, e.g. histamine (particularly foregut), tachykinins (Substance P), bradykinins, and prostaglandins.

If you study the online forums, there are frequent questions about flushing, particularly from those looking for a diagnosis and are suspecting Carcinoid due to a flushing symptom. However…… even flushing cannot always be attributed to Carcinoid, particularly if it’s the only symptom being presented.

Flushing tests

This is a very useful table taken from my amazing yellow book which gives the tests required to determine the potential source of a flushing (differential diagnosis).  I strongly suspect this is not an exact science (…..is anything in medicine?) but it’s extremely useful.  Personally I would have included Rosacea 🙂

My own experience with flushing brings back some memories and it emphasises something I say a lot – the patient has a big part to play in their own diagnosis.  Please check out this 90 second video about how I did not play my part!  I was experiencing a mild and innocuous flushing sensation for some months before I was diagnosed with metastatic Neuroendocrine Cancer.  Even though I knew it was weird and something I hadn’t experienced before, I totally ignored it.  I failed to mention it at any of my routine GP appointments or my annual asthma clinic.  I failed to mention it to my specialist who was investigating a GP/PCP diagnosis of Iron Deficiency Anemia/weight loss.  After a CT scan, the specialist appeared to be scratching his head …..  at that point he knew I had cancer but he also knew it was unusual.  I suddenly mentioned the flushing and ‘bingo’.  It was the face of a man who had just found a missing piece of a jigsaw and he correctly predicted the output from my subsequent liver biopsy.

For the next few months, I was keeping my condition private at work but it was sometimes difficult to disguise the flushing. At least  one person thought my blood pressure was going up! Fortunately, my flushing disappeared after treatment.

I’ll complete this post with an interesting summary from an online forum post in which I was participating. There was a general discussion about the severity of ‘syndrome symptoms’ including triggers and I was staggered to read that people were experiencing flushing whilst carrying out routine day-to-day tasks. I’m so happy I don’t flush when I eat one square of chocolate (that would be a complete disaster!).  The one which caught my attention was the simple act of washing hair. Whilst I initially raised my eyebrows and laughed, it did make me think back to the last flush I experienced (and touch wood it was the last …..).  Following my diagnosis, I commenced daily injections of Octreotide. These injections reduced the flushing but it didn’t eliminate it. However, after my ‘debulking’ surgery in Nov 2010, my flushing disappeared.  However, I do remember this small flush coming out of nowhere whilst I was recovering in hospital after that surgery. I was cleaning my teeth and I do vividly remember this minor task taking some effort!

I haven’t had a flush since and if this symptom comes back, I’ll know I have a new problem to contend with.

Thanks for listening

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