The Invisible NET Patient Population 

The Invisible NET Patinet Population

OPINION

 

I found some of the quotes from the recent NET SEER Database study (Dasari et al) very interesting.  The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program is a comprehensive source of population-based information initiated in 1973 that is updated annually. Although the study is US-based, it represents the largest study of Neuroendocrine Tumors (NETs) ever recorded and is therefore a good guide to what might be found beyond USA. In fact, other national declarations of incidence and prevalence of NETs seem to bear these statistics out, i.e incidence rates of 7-8/100,000 …… almost 7 times the rate recorded in the 1970s. If you want to understand the factors behind this massive increase, I covered this extensively in my post “Neuroendocrine Tumors – not as rare as you think“.  In this article, I looked at USA and beyond. Those who are regular readers of my articles will already know I’ve been ‘banging on’ about this for a few years. Other organisations and individuals (including NET specialists) are now indicating these tumors are not rare, some vindication for my aforementioned ‘banging on’.  This is now a serious disease with some serious statistics behind it and we need a new way of doing things.

 There are two further quotes which I’d like to focus on in this article:

1. From the NET SEER Database study published 2017:

…… many cases of NETs may not have been reported to cancer registries unless considered malignant…… it is likely that we have underestimated their true incidence and prevalence” – i.e. the slide here:

SEER 2012 Underestimated

2. From Dana Farber (Kulke, Chan):

“Estimated more than 200,000 undiagnosed cases in the US” – this slide here:

dana-farber-200000

…. But what do these quotes actually mean?  Here’s my take:

Underestimating the true incidence and prevalence of NETs

I studied the latest SEER NET study, formally titled “Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States” (authored by Arvind Dasari, MD, MS; Chan Shen, PhD; Daniel Halperin, MD; et al). From this document, I can see the authors were aware of the well-known faults in cancer registries worldwide and the effect this has on the true incidence and prevalence of Neuroendocrine Cancer.  These issues, which are a worldwide problem, include the incorrect registration of Neuroendocrine Cancer as other types based on the anatomical location of the primary tumor.  At this point, you may wish to check out my post “The Human Anatomy of Neuroendocrine Cancer” which provides some real life examples of the confusion between primary Neuroendocrine location and other cancers. That said, things are definitely improving because the latest SEER data shows a marked increase in the incidence of High Grade Neuroendocrine Carcinomas (NEC), an area where this issue is prevalent. A similar increase in NEC was also illustrated in the UK’s figures from Public Health England (PHE) in 2016 (click here) indicating that cancer registries are getting better and not before time, although it has to be said this only came about due to a major intervention by NET Patient Foundation and others. Through this work, it’s becoming clear that the incidence of all NETs in UK is around 8 to 9 per 100.000 (rare threshold <=5).

But there’s another issue impacting whether a diagnosis is actually entered on a cancer registry or not.  Unfortunately, there are members of the medical community who still see well differentiated NETs as benign tumors, ‘not a proper cancer’ and still use ancient terminology ………  ‘Carcinoid’.  The WHO 2010 classification for NETs was based on the concept that all NETs have malignant potential. Here’s a quote from the UKINETS Guidelines in 2011 (Ramage, Caplin, Meyer, Grossman, et al).

Tumours should be classified according to the WHO 2010 classification (Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010). This classification is fundamentally different from the WHO 2000 classification scheme, as it no longer combines stage related information with the two-tiered system of well and poorly differentiated NETs. The WHO 2010 classification is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential.

The guidance in WHO 2017 for Endocrine Organs reinforces this statement.

The undiagnosed NET patient population

From above, you can see why the incidence (and therefore the prevalence) of our disease has almost definitely been underestimated.  However, that’s not the end of my story……..

A number of statements are clear about Neuroendocrine Tumors:

  • Low/Intermediate grade well differentiated tumors are known to have been growing slowly over a number of years before discovery or accurate diagnosis occurs,
  • They can be difficult to diagnose,
  • They are not that well-known amongst the general medical population,
  • Many people are initially misdiagnosed with another condition, with some this will result in late presentation with metastatic disease.
  • Many NETs are found during autopsies.

The living undiagnosed. It’s worth pointing out that one of the conclusions made by the recent SEER NET study is that the increase in incidence and prevalence can be attributed to a number of factors including earlier diagnosis.  This is of course excellent news.  Also worth noting that another conclusion of the study is that we are all living longer, reflecting improvements in therapies.  This is also great news and is a factor in increased prevalence figures. However, it seems obvious that there are hundreds of thousands of people out there still be diagnosed who have tumors silently growing inside them and who are in a loop of referrals between primary and secondary care awaiting a proper diagnosis. See the Dana Farber slide above.  Please help these people by sharing this article (you never know who it will reach – Diagnosing the Undiagnosed.

The dead undiagnosed? The true incidence of NETs may be much higher owing to the lack of diagnosis until after death.  For example:

  • In USA, a respected NET specialist stated that the autopsy find for (excuse the outdated terminology…….) ‘carcinoid‘ is 4 times the recorded diagnosis rate (based on the known incidence rate at the time, this is 8 per 100,000).
  • In Australia, one study claimed that 0.05% of all autopsies found a Pheochromocytoma or Paraganglioma. “
  • The Mayo Clinic experience shows that in up to 50% of cases of pheochromocytoma, the correct diagnosis is made at autopsy (ergo the incidence rate could be double what is published).
  • Here is an article claiming that former US President Dwight D Eisenhower had a biopsy confirming he had a Pheochromocytoma.  Click here.
  • A Hong Kong study indicated that 1% of all autopsies discovered an ‘Islet Cell’ tumour (i.e. a Pancreatic NET or pNET).
  • In one series, (excuse the outdated terminology…….) ‘carcinoid’ tumors were found in 1.22% of 16,294 autopsies in Malmö, Sweden, 90% of which were incidental findings.

It’s possible that many of these people showed no NET symptoms during their life but …… it’s equally possible that many of these people had NET symptoms but just put up with it and/or had been diagnosed with something else, and then died without a correct diagnosis.  There is no evidence that any investigation follow ups were done so this possibility remains.

The potential for even more undiagnosed. To add to the underdiagnoses of NETs issue, is this most amazing piece of research published in 2018 – Pan-cancer molecular classes transcending tumor lineage across 32 cancer types, multiple data platforms, and over 10,000 cases.  It was published in the American Association of Cancer Research (AACR) journal ‘Clinical Cancer Research and authored by Chad Creighton et al. D.  This was a pan-cancer piece of research which indicated that Neuroendocrine disease may be more prevalent than anyone has ever thought.  There’s a summary article here which I suggest you read fully.  The rather explosive extract is as follows:

We expected that about 1 percent of

Are you undiagnosed but suspect NETs?

Check out my advice by clicking here.

Summary

I suspect there’s an invisible patient population for many conditions but the slow-growing and relatively quiet nature of Neuroendocrine Cancer means there could be a significant undiagnosed burden walking around, looking for a diagnosis, putting up with symptoms and being treated for other conditions. I see people on forums looking for clues, social media can sometimes be helpful here. That said, I do get the feeling some do not have NETs, regardless of the symptoms they associate with the disease, but I guess many of them will go on to be formally diagnosed with something. I’m contacted by many ‘undiagnosed’ people on my own blog and supporting Facebook sites (mostly privately) and I can tell you that’s a tough gig.  I only hope I’ve given them some useful ideas about where to look or what to ask/suggest.

I feel earlier diagnosis reported in the SEER study is partly due to increased awareness, particularly in the medical world. I would also suggest that it has improved in the general population due to the explosion of social media information dissemination. It’s also accurate to say that improvements in diagnostic capabilities is also playing its part in pushing up incidence rates, just as improved therapies have pushed up prevalence rates, something emphasised by Dasari (et al) in the most recent study.  Things are improving but there is so much more to do.

The issues caused by inefficient registries together with ‘the undiagnosed’, combine to suggest there is a large invisible NET patient population out there ……. we just need to find them!  

Thanks to NET Patient Foundation for featuring this article here.

NET Patient Foundation logo

Neuroendocrine Tumours – benign vs malignant

Kunz His belief these tumors did not metastisize

OPINION:

One of the most controversial aspects of Neuroendocrine Tumours (NETs) is the ‘benign vs malignant’ question.  It’s been widely debated and it frequently patrols the various patient forums and other social media platforms. It raises emotions and it triggers many responses ….. at least from those willing to engage in the conversation. At best, this issue can cause confusion, at worst, it might contradict what new patients have been told by their physicians (….or not been told). I don’t believe it’s an exact science and can be challenging for a NET specialist let alone a doctor who is not familiar with the disease.

NANETS Guidance talks about the ‘…heterogeneous clinical presentations and varying degrees of aggressiveness‘ and ‘…there are many aspects to the treatment of neuroendocrine tumours that remain unclear and controversial‘.  I’m sure the ‘benign vs malignant’ issue plays a part in these statements.

In another example, ENETS Guidance discusses (e.g.) Small Intestine Tumours (Si-NETs) stating that they ‘derive from serotonin-producing enterochromaffin cells. The biology of these tumors is different from other NENs of the digestive tract, characterized by a low proliferation rate [the vast majority are grade 1 (G1) and G2], they are often indolent’.  However, they then go on to say that ‘Si-NETs are often discovered at an advanced disease stage – regional disease (36%) and distant metastasis (48%) are present‘.  It follows that the term ‘indolent‘ does not mean they are not dangerous and can be ignored and written off as ‘benign’. This presents a huge challenge to physicians when deciding whether to cut or not to cut.

Definitions

To fully understand this issue, I studied some basic (but very widely accepted) definitions of cancer.  I also need to bring the ‘C’ word into the equation (Carcinoid), because the history of these tumours is frequently where a lot of the confusion lies.  The use of the out of date term ‘Carcinoid’ exacerbates the issue given that it decodes to ‘carcinoma like‘ which infers it is not a proper cancer.  See more below.

Let’s look at these definitions provided by the National Cancer Institute.  Please note I could have selected a number of organisations but in general, they all tend to agree with these definitions give or take a few words. These definitions help with understanding as there can be an associated ‘tumour’ vs ‘cancer’ debate too.

Cancer – Cancer is the name given to a collection of related diseases. In all types of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues. There are more than 100 types of cancer which are usually named for the organs or tissues where the cancers form.  However, they also may be described by the type of cell that formed them.

Author’s note: The last sentence is important for Neuroendocrine Tumour awareness (i.e. Neuroendocrine Tumour of the Pancreas rather than Pancreatic Cancer).

Carcinoma – Carcinomas are the most common grouping of cancer types. They are formed by epithelial cells, which are the cells that cover the inside and outside surfaces of the body. There are many types of epithelial cells, which often have a column-like shape when viewed under a microscope.

Author’s note: By definition, Carcinomas are malignant, i.e. they are cancers. High Grade (Grade 3) poorly differentiated “NETs” are deemed to be a ‘Carcinoma’ according to the most recent World Health Organisation (WHO) classification of Neuroendocrine Tumours (2017) and ENETS 2016 Guidance. You will have heard of some of the types of Carcinoma such as ‘Adenocarcinoma’ (incidentally, the term ‘Adeno’ simply means ‘gland’). It follows that Grade 3 Neuroendocrine Carcinomas are beyond the scope of this discussion.

Malignant – Cancerous. Malignant cells can invade and destroy nearby tissue and spread to other parts of the body.

Benign – Not cancerous. Benign tumors may grow larger but do not spread to other parts of the body.

Author’s Note: This is a key definition because there are people out there who think that low grade NETs are not cancer. 

Tumour (Tumor) – An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancerous), or malignant (cancerous). Also called Neoplasm.

Author’s Note: Neoplasm is an interesting term as this is what is frequently used by ENETS and NANETS in their technical documentation, sometimes to cover all Neuroendocrine types of cancer (Tumor and Carcinoma). It follows that a malignant tumour is Cancer. The term “Malignant Neuroendocrine Tumour” is the same as saying “Neuroendocrine Cancer”

Neuroendocrine Tumours – Benign or Malignant?

Definitions out of the way, I have studied the ENETSUKINETS and NANETS guidance both of which are based on internationally recognised classification schemes (i.e. the World Health Organisation (WHO)).

In older versions of the WHO classification schemes (1980 and 2000), the words ‘benign’ and ‘uncertain behaviour’ were used for Grades 1 and 2. However, the 2010 edition, the classification is fundamentally different (as is the recent 2017 publication).  Firstly, it separated out grade and stage for the first time (stage would now be covered by internationally accepted staging systems such as TNM – Tumour, (Lymph) Nodes, Metastasis). Additionally, and this is key to the benign vs malignant discussion, the WHO 2010 classification is based on the concept that all NETs have malignant potential.  Here’s a quote from the UKINETS 2011 Guidelines (Ramage, Caplin, Meyer, Grossman, et al).

Tumours should be classified according to the WHO 2010 classification (Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010). This classification is fundamentally different from the WHO 2000 classification scheme, as it no longer combines stage related information with the two-tiered system of well and poorly differentiated NETs. The WHO 2010 classification is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential.

The guidance in 2017 WHO reinforces this statement to include endocrine organs, including the pancreas and adrenal glands.

The C Word (Carcinoid) – part of the problem?

History lesson – Carcinoid tumours were first identified as a specific, distinct type of growth in the mid-1800’s, and the name “karzinoide” was first applied in 1907 by German pathlogist Siegfried Oberndorfer in Europe in an attempt to designate these tumors as midway between carcinomas (cancers) and adenomas (benign tumors).

The word ‘Carcinoid’ originates from the term ‘Carcinoma-like’.  ‘CARCIN’ is a truncation of Carcinoma. ‘OID’ is a suffix used in medical parlance meaning ‘resembling’ or ‘like’.  This is why many people think that Carcinoid is not a proper cancer.

The situation is made even more confusing by those who use the term “Carcinoid and Neuroendocrine Tumors” inferring that it is a separate disease from the widely accepted and correct term ‘Neuroendocrine Tumor’ or Neuroendocrine Neoplasm.  A separate discussion on this subject can be found in this post here. I encourage you to stop using the term ‘Carcinoid’ which is just perpetuating the problem. 

Kunz His belief these tumors did not metastisize

How are NETs Classified?

If you read any NET support website it will normally begin by stating that Neuroendocrine Tumours constitute a heterogeneous group of tumours. This means they are a wide-ranging group of different types of tumours.  However, the latest WHO classification scheme uses the terms ‘Neuroendocrine Tumour’ for well differentiated Grade 1 (low-grade), Grade 2 (Intermediate Grade) and Grade 3 (High Grade) NET; and ‘Neuroendocrine Carcinoma’ for Grade 3 (High Grade) poorly differentiated tumours. They also use the term ‘Neoplasm’ to encompass all types of NET and NEC. So Grade 1 is a low-grade malignancy and so on (i.e any grade of NET is a malignant tumour).  You may benefit from reading my blog article on Staging and Grading of NETs as this is also a poorly understood area.

Can some Tumours be Benign?

By any accepted definition of cancer terms, a tumour can be non-cancerous (benign) or cancerous (malignant).  This is correct for any cancer type. For example, the word is used in the 2016 version of Inter Science Institute publication on Neuroendocrine Tumors, a document I frequently reference in my blog.  For example, I’ve seen statements such as “These tumors are most commonly benign (90%)” in relation to Insulinoma (a type of Pancreatic NET or pNET). Ditto for Pheochromocytoma (an adrenal gland NET).  Adrenal and Pituitary ‘adenomas’ are by definition benign (adenoma is the benign version of Adenocarcinoma).  And I note that there is a ‘benign’ code option for every single NET listed in the WHO International Classification of Diseases (ICD) system.

The ‘BUT’ is this – all WHO classification systems are based on the concept that all NETs have malignant potential.  The WHO 2017 classification update confirmed this thinking by adding endocrine organs including the pancreas and adrenal glands.

don't worry it's benign widescreen

Can Tumours be Malignant or become Malignant?

Using the definition above, if a tumour invades and destroy nearby tissue and spread to other parts of the body, then it’s malignant (i.e  Cancer). However, there’s a reason why the WHO declared in 2010 that all NETs have malignant potential (as amplified in WHO 2017). It may not happen or it may happen slowly over time but as Dr Richard Warner says, “they don’t all fulfill their malignant potential, but they all have that possible outcome”.  Thus why ongoing surveillance is important after any diagnosis of Neuroendocrine Tumour of any grade or at any stage.  Dr Lowell Anthony, a NET Specialist from the University of Kentucky explains this much better than I can – CLICK HERE to hear his two-minute video clip.

Summary

This was a difficult piece of research. I do believe there are scenarios where NETs will be benign and probably never cause the person any real harm (e.g. many are found on autopsies). I  suspect this is the same for many cancers. However, based on the above text and the stories of people who have presented for a second time but with metastatic disease, use of the word ‘benign’ is probably best used with great care.

I would certainly (at least) raise an eyebrow if someone said to anyone with any NET tumour, “you don’t need any treatment or surveillance for a NET”; or “it has been cured and no further treatment or surveillance is required”.  Particularly if they are not a NET specialist or a recognised NET Centre.

Remember, I’m not a medical professional, so if you are in any doubt as to the status of your NET, you should discuss this directly with your specialist.  A good place to start is evidence of your Grade, Differentiation, Primary Site Location and Stage.

You may be interested in reading these associated posts:

Carcinoid vs Neuroendocrine

Neuroendocrine Neoplasms – Grading and Staging (WHO 2017)

Incurable vs Terminal

10 Questions for your doctor

Thanks for listening

Ronny

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Neuroendocrine Cancer: Hurry up and wait


hurry-up-and-wait

When I was diagnosed with metastatic Neuroendocrine Cancer on 26 July 2010, I just wanted them to hurry up and fix my body so I could get back to normal. That’s what happens to cancer patients with distant metastases is it not? My expectations of what should happen turned out to be wildly inaccurate and in hindsight, I was also wildly naive. You see, with Neuroendocrine Cancer, particularly well-differentiated, low or medium grade tumours, it sometimes doesn’t work as fast as you would think.

The complexity of the condition needs some consideration as the physicians work up a treatment plan. I’m quite happy and content they took their time, rather than rush into the wrong decisions. If you think about it, this is an advantage with low and medium grade NETs……you normally have some time.

Here’s a very short video discussing this during a patient video shoot: Click here.

I had a confirmed biopsy result following some incidental CT scans and other tests. However, they now needed further checks and marker tests to work out the extent of the disease. So the timeline leading up to major surgery ended up like this:

Diagnosis: 26 July 2010.  Grade 2 Small Intestine NET with distant metastasis (Stage 4)

Chromogranin A and 5HIAA: submitted 28 July. Results received 13 Aug – both elevated, indicating and confirming tumour bulk and function status respectively

Octreotide Scan: 17-19 August. Report issued 24 August – confirmed CT plus additional distant hotshots. Also confirmed my tumour receptors were avid to somatostatin analogues.

Daily Octreotide Injections: Started 9 September to control syndrome (derisk surgery)

Referred to NET Multi-Disciplinary Team (MDT): 15 September – they now had sufficient data to form a treatment plan.

Holiday:  Late September (it was booked and I felt OK, why not!)

Further MDT assessment: 1- 7 October

Bland Liver Embolisation: 19 October

First Surgery: 9 November – to remove primary and debulk local and regional spread.

You can read the rest of my treatment background here.

So it took 75 days from diagnosis to opening me up to remove the first batch of tumours. With reasonably slow-growing tumours, that isn’t really a long time when you consider they had probably been growing inside me for several years. I’m sure others waited even longer.

Sometimes rushing straight into the operating theatre isn’t really the best option.  I’m still here!

Keep calm and hurry up and wait!

Thanks for reading

Ronny

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Neuroendocrine Cancer – Incurable vs. Terminal

Incurable is not untreatable

OPINION. When I was being officially told I had an advanced and incurable cancer, I did what most people seem to do on films/TV ….. I asked “how long do I have“.  The Oncologist said ” … perhaps just months“.  That must have been quite a shock because for a few moments after that, I heard nothing – my brain was clearly still trying to process those words – I wasn’t even feeling unwell! The really important bit I missed was him go on to say “…but with the right treatment, you should be able to live for a lot longer”.  Fortunately, my wife Chris heard it all and I was refocused.  “OK Doc – let’s go” I said.  Always take someone with you to take notes at important meetings with Oncologists!

I continue to see quite a few posts and articles about death and dying and I noticed some patients were using the word ‘terminal‘ to describe Neuroendocrine Cancer, despite in some cases, having been diagnosed some years ago. This label is not just confined to use within Facebook forums, I’ve also seen this on wider social media including twitter, blogs and newspaper items. For some, this appears to be the prognosis given to them by their doctors. I find this surprising. However, I’m much less surprised to see many comments on forums from people who had been told the worst by their doctors but were still alive and kicking WAY beyond those worst case prognostic statements.

Definitions are important so what does ‘terminal cancer’ actually mean? 

I’m conscious there are legal ramifications with the definitions (wills, life insurance, disability etc) and that these may differ on an international/federal basis.  I therefore intentionally confined my searching to a couple of ‘big hitter’ and ‘authoritative’ sites:

Cancer Research UK defines terminal as “When cancer is described as terminal it means that it cannot be cured and is likely to cause death within a limited period of time. The amount of time is difficult to predict but it could be weeks to several months”.

The American Cancer Society defines terminal as “an irreversible condition (it cannot be cured) that in the near future will result in death or a state of permanent unconsciousness from which you are unlikely to recover. In most states, a terminal illness is legally defined as one in which the patient will die shortly whether or not medical treatment is given.”

Can terminal as defined above be applied to Neuroendocrine Cancer? 

I’m sure it can, e.g. with very advanced and very aggressive disease and for any grade when taking into account the condition of the patient and other factors (secondary illnesses/comorbidities, refusal of treatment etc). Clearly, that is a terrible situation.  I’m also conscious that some people do eventually die because of this disease or its consequences and that is also terrible.

How long is a piece of string?

I think with most Neuroendocrine Cancer patients, “how long do I have” can be a tough question to answer. Thinking back to my own situation, although it was an obvious question to ask my Oncologist, I can see it might have caught him unawares.  I suspect he was erring on the side of caution as I don’t believe he had formulated my treatment plan ….. i.e. my case had not yet been looked at by a Multi-Disciplinary Team (MDT), a bit like a ‘Tumor Board’.  I had already been confirmed Grade 2 (via liver biopsy) and my CT scans were indicating widespread disease.  I was yet to have an Octreotide scan and the conventional biochemical markers (CgA and 5HIAA).  I suspect, faced with my question, he went for the worst case, based on the statistics he had access to at the time. What I now know is that, in the year of my diagnosis, the median survival was 33 months in patients with advanced Grade 1/Grade 2 NETs with distant metastasis.  These statistics are certainly better today but my Oncologist was probably on the right track.  However, at no time did he use the word ‘terminal’.

The Cancer story is changing

What I also found during my research is that as more and more people in the UK are now living with cancer (all cancer) rather than dying from it, there is a new class of patients emerging – Macmillan UK call this “treatable but not curable” and I believe this is very relevant to Neuroendocrine Cancer.  I touched on this in an awareness blog entitled “Living with Neuroendocrine Cancer – it takes guts“.  You will find some data in this blog about a major increase in the amount of people with cancer who eventually die of something else (…… basically it has doubled). For many, Cancer is no longer a death sentence.  I do accept that it can be difficult to live with certain cancers and this is also covered in my “it takes guts” blog linked above.

Survivorship and Hope

You can find numerous examples of long-term survivors of advanced Neuroendocrine Tumours on the ‘airwaves’, many with a relatively good quality of life (QoL).  I don’t normally pay much attention to prognostic data, I take my lead from the huge number of patients living a long time with Neuroendocrine Cancer.  However, I was particularly interested to read a set of USA statistics from NOLA (Boudreaux, Woltering et al) which said “Our survival of stage IV midgut NET patients that we performed surgical debulking on was published in the Journal of the American College of Surgeons in 2014. It showed our 5, 10 and 20-year survival rates were 87%, 77% & 41% respectively. It’s also worth noting the comparison with the 2004 SEER database analysis which listed the 5 & 10 year SEER survival at 54% and 30% respectively”.  Clearly, the NOLA figures are guidelines (and only for midgut) but they do seem to reflect my previous statement about seeking out positives rather than dwelling on the negatives.  The SEER 2012 figures stated “Survival for all NETs has improved over time, especially for distant-stage gastrointestinal NETs and pancreatic NETs in particular, reflecting improvement in therapies.

Exciting times ahead

Recently, there’s been a plethora of new treatments coming online and more entering and progressing through the approvals pipeline.  Check out my blog entitled Exciting Times Ahead Also listen to a NET Expert along the same lines.

Summary

Following my diagnosis in 2010, I went on to receive really good treatment and it continues to this day with Lanreotide backed up by a rigorous surveillance regime (and this is backed up by my own advocacy!).  However, I have totally accepted the fact that I have metastatic Neuroendocrine Cancer and that it cannot be cured.  By the way, I intentionally used ‘metastatic’ rather than Stage IV.  Mention of Stage IV can set off alarm bells and therefore send the wrong message to the recipient. I don’t believe Stage IV has the same ‘red flag’ meaning for well-differentiated NETs as it does with more aggressive cancers of the same stage. Given what I know now, I would certainly challenge any doctor who told me I had a ‘terminal disease’ and also told me I had a slow-growing well differentiated Neuroendocrine Cancer.

I live with this disease (….and it’s consequences) and do not feel like I’m dying of it.  Moreover, I most certainly do not see myself as a ‘terminal’ cancer patient, particularly as I’ve now been living with it for almost 8 years. Rather, I like to focus on how I can live better with it.

Whilst we’re on this subject, please note Palliative Care is not just end of life / hospice care.  That’s another misunderstanding bordering on mythical status. Read more here.

being_there_front
Graphic courtesy of Ellie McDowell

 

Thanks for reading

Ronny

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

Grades of Neuroendocrine Tumour WHO 2017 15 Dec 2017

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, grade and differentiation of my cancer”.  To enable me to synchronise with the documented guidance, I’m going to use the following WHO 2017 approved terms in this post:

  • Neuroendocrine Neoplasm (NEN) – all types of Neuroendocrine tumour of whatever grade (please note Neoplasm is another word for tumour)
  • Neuroendocrine Tumour (NET) – all well-differentiated tumours (an explanation of differentiation will be provided below)
  • Neuroendocrine Carcinoma (NEC) – all poorly differentiated tumours

NEN Breakdown

Stage vs Grade

In the most basic of terms, stage is the spread or extent of cancer and grade is the aggressiveness of cancer. They are totally different things and an understanding of both is important as they are 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 (actually very common with NETs).

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.

Why is differentiation important?

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. The differentiation of a NET has an impact on both prognostics and treatment regimes.

NENs 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 (but see below for Lung NETs). 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 (what some might ‘old fashionably’ and incorrectly refer to as Lung 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 differentiation levels to 2.  Grade 2 is also defined as well differentiated but based on different proliferative rate (see table). High grade was normally referred to as Neuroendocrine Carcinoma indicating it is a faster growing and more aggressive cancer. However, see below for an important change to high grade classification.

Grading – Key WHO 2017 Changes

WHO Classifications of Cancer are published in something known in medical world as “The Blue Book”.  For NETs, the 2017 version comprises only the “WHO Classification of Tumours of Endocrine Organs”.  Technically this would preclude the digestive system and lung NETs but I’m told on good authority from world leading pathologists and from listening to lectures at ENETS 2018, that the classification in the leading picture is to be used for all NENs. Worth also noting that the latest ENETS Guidelines are already using the new grading terms.  Many sites remain out of date so be careful where you look.

The 2017 World Health Organisation (WHO) classification sub-divided Grade 3 into two new entities: a well differentiated high-grade NET and 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 in relation to potential treatment strategies (55% is mentioned for pNETs but I’m currently investigating).

The Grade 1 to 2 Ki-67 cut-off is changed from 2 to < 3 for clarification purposes.  There was some discussion as to whether it should be <5 but this was not accepted.

Well differentiated High Grade NETs are now recognised.  These are known as a NET rather than a NEC.  Both Grade 3 (NET) and Grade 3 (NEC) have the same biopsy marker cut-offs as per the leading slide but it is thought that a threshold reading of 55% could have some influence on the treatment regime. For example, a well differentiated tumour with a Ki67 of less than 55% might benefit from the same treatment given to Grade 1 or 2 patients, whereas a well differentiated tumour with a Ki67 of less than 55% might benefit from the same treatment given to poorly differentiated NEC. I suspect this is like many things in NENs, very individual, relies on many factors, so your specialist will drive this accordingly.  You may see these 2 grades listed as Grade 3a for NET and Grade 3b for NEC.

Previously, Pheochromocytoma did not have an official grading regime, i.e. they were just benign or malignant.  Now they are using the same grading system as above.  I’m assuming this is the same for Paraganglioma and I will confirm in due course.  This is an excellent change and a continuation from the WHO 2010 classification where there was great emphasis away from a benign/malignant classification to formal grade levels on the basis that all NETs have malignant potential.

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’ has been chosen rather than ‘Carcinoma’ is because these neoplasms can be well or poorly differentiated.

It’s not possible at this time to acquire copies of the official output but I will keep this blog live.

The source material for the 2017 version of this article.

From leading Pathologist Dr Anthony Gill  – Remember this is based on Endocrine Organs only but it will eventually apply to all.   I am awaiting access to free documentation to update this article further – only ones I can currently find are not free!

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 indicating a rising spread as the number is bigger. Often doctors write the stage down in Roman numerals, perhaps this is to stop any confusion between standard numbers used for Grades? So you may see stages written as I, II, III and 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 when I can free access.

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

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

Stage IV 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 IV does not necessarily mean a cancer is more dangerous than other cancers of lesser stages.  This is an important point for NETs where Stage 4 can be matched up 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 IV NET, while surgery might not help a patient with a cancer of a higher grade 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:

This slide will be updated when I get access to WHO 2017 or updated AJCC pubication.

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 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:

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.

You may benefit from reading these associated posts:

Benign vs Malignant

Incurable vs Terminal

Carcinoid vs Neuroendocrine

10 Questions for your doctor

Looking for a needle in a haystack

Thanks for reading

Ronny

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