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  The use of the out of date term ‘Carcinoid’ exacerbates the issue given that it decodes to ‘carcinoma like‘ which infers it is not a proper cancer.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 – not as rare as you think

Background

Although initially considered rare tumours up until 10 years ago, the most recent data indicates the incidence of NETs has increased exponentially over the last 4 decades and they are as common as Myeloma, Testicular Cancer, and Hodgkin’s Lymphoma. In terms of prevalence, NETs represent the second most common gastrointestinal malignancy after colorectal cancer. Consequently, many experts are now claiming NETs are not rare (see below).  A recent study published on 5 Dec 2018 reports that even if you isolate Small Intestine NETs in the USA population, the incident rate is 9/100,000. Contrast this against the US incident rate as at 2012 of 7/100,000 for all NETs.  The rare threshold in Europe is 5/100,000 and below.

And on 7th January 2019, an internationally known NET Specialist described NETs as very common.

strosberg not rare
In fact, the graph of the SEER database figures for NETs in both 2004 and 2012 indicates the rate of incidence increase is faster than any other cancer on the planet, particularly attributed to lung, small intestine, and rectal NETs.  The World Health Organisation’s revised classification of Neuroendocrine Neoplasms in 2010, abandoned the division between benign and malignant NET as all NETs have malignant potential and should be graded accordingly.  The 2004 SEER data compiled did not take into account what might have been considered to be benign NETs.

However, the most recent USA study up to 2012 has confirmed the incidence beyond 2004 has continued to rise (and rise, and rise, and rise) and this is covered below in the section entitled “Meanwhile in USA”. One of the principal authors of both database studies has now gone public and said NETs are no longer rare. 

Incidence and Prevalence

Before I continue, it’s important to understand the difference between incidence and prevalence.  In the crudest of terms, incidence is the number of new cases of a disease being diagnosed (normally aligned to a specific quota of the population per year, generally 100,000). Prevalence normally indicates an amount of people living at any one time with a disease. It’s also important to note that different nations or groups of nations classify ‘rare’ in different ways – not really helpful when looking at worldwide statistics.

So why the increase?  I suspect the reasons include (but are not limited to), more awareness (population and medical staff), better detection techniques and probably more accurate reporting systems, at least in USA, Norway, Canada and now in the UK i.e. a mixture of underdiagnoses and misreporting.  The Canadian study is important as it also noted the proportion of metastases at presentation decreased from 29% to 13%. This is the first study that suggests an increased incidence of NETs may be due to an increased (and earlier?) detection. This has the knock on effect of increasing prevalence as most NET Cancer patients will normally live for longer periods.  Add to this the plethora of better treatments available today, you have a highly prevalent cancer. Most of that is good news.

However, their true incidence may be 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. In Australia, one study claimed that 0.05% of all autopsies found a Pheochromocytoma or Paraganglioma.  A very interesting slideshow from a well respected NET expert claimed there are 200,000 undiagnosed NET patients in USA. Slide below:  You may also wish to check out my article “The Invisible NET Patient Population” where this is explored further.

dana-farber-200000

US SEER 2004 – The Trigger and Turning Point

In the largest study of its kind up to that point, well-known Neuroendocrine Cancer expert James C. Yao researched the Surveillance, Epidemiology and End Results (SEER) database. His team studied 35,825 cases of Neuroendocrine Cancers in the United States covering data between 1973 and 2004. The report concluded that in 2004 there were 5.25 new cases of NETs per 100,000 people, compared with 1.09 per 100,000 in 1973 [1]. This is in contrast to the overall incidence of malignancies, which has remained relatively constant since 1992 (see the yellow line on the graph). The study also pointed out that due to increased survival durations over time, NETs are more prevalent than previously reported. If you analyse the NET data for 1994 (10 years before the end of the study period), you will see an incidence rate of approx 3.25/100,000. In 2004, the incidence rate had risen to 5.25/100,000. Although not an exact science, it does suggest the potential incidence rate at 2014 (10 years after the study period) might possibly have climbed well beyond 6/100,000 and even further if the same rate of increase displayed by the study had continued (spoiler alert – it actually came out as 7/100,000 see below under ‘Meanwhile in USA’). This study also confirmed a prevalence of 103,000 NET patients as at 2004. As this is regarded as the most accurate NET statistic ever produced, it is interesting to note that was at a time when the prognostics for NET were not as good as they are today indicating there must be a very significant increase if extrapolated to the current time. Moreover, this was prior to the WHO 2010 reclassification of NETs so more diagnoses will be counted today that were not counted in 2004. See below to see the significance of this figure (see section ‘Do the math’).

The 2004 data was an astonishing set of statistics – particularly as they were based on 12 year old data. However, there is now new data up to 2012 that overtakes the above-mentioned groundbreaking study and confirmed the incidence is now even higher.  See section entitled “Meanwhile in USA …….” 

incidence
SEER study 2004 – NETs

Meanwhile in Norway ……

Data from the Norwegian Registry of Cancer showed a similar incidence of Neuroendocrine Cancers with a 72% increase between 2000 and 2004 compared with 1993–1997 [2]. Also in Norway, an article published in 2015 entitled “Epidemiology and classification of gastroenteropancreatic neuroendocrine neoplasms using current coding criteria” indicated a high crude incidence of GEP-NEN, at 5·83 per 100 000 inhabitants over the period 2003-2013 (adjusting to 7.64 for Europe in 2013 – see diagram below extracted from cited article 2a).  It was also noted together with the statement “….a significant increasing trend over time”. [2a] Citation [2b]
extrapolation europe

Meanwhile in Canada …….

CNETs have highlighted an article published in the magazine ‘Cancer’, February 15, 2015, showing that the incidence of Neuroendocrine Tumours has markedly increased in Canada over the course of 15 years (1994-2009). The results showed that the incidence of Neuroendocrine Tumours has increased from 2.48 to 5.86 per 100,000 per year. [3] [4]

simron singh nets not rare

Meanwhile in UK …….

The latest figures from Public Health England (PHE) indicate the incidence of NETs has risen to almost 9/100,000 (i.e. not rare) using the latest International Classification of Diseases for Oncology (ICD-O) methodology version 3 – ICD-O-3. Even that figure is understated because it does not include Lung Neuroendocrine Carcinomas (i.e. SCLC and LCNEC). As at 31 Mar 2016, the age-standardised incidence rate for NETs in England (excluding small and large cell neuroendocrine carcinomas, SCLC and LCNEC respectively) was 8.84, 8.37 in males and 9.30 in females – rising from 3.9 in 2001.  These figures are from the NET Patient Foundation and were issued as a result of a NPF and PHE (NCRAS) partnership project which has been compiling statistics on the incidence, prevalence and survival of NET Patients in England using English cancer registry data. They also have an aim to also access the rest of UK cancer registry data to get UK wide figures.

That means a new NET diagnosis every 2 hours. You can see a summary of the report   NEW:  Public Health England release new incidence data for Neuroendocrine Cancer

A slide from the recent UKINETS 2017 conference indicating an agreement from UK and Ireland NET Specialists.

IMG_20171204_214918
as presented at UKINETS 2017

Meanwhile in New Zealand …….

as presented by Unicorn Foundation NZ on 11 Mar 2017

Meanwhile in USA …….

The latest evidence of its rise is contained in the largest ever study ever conducted. It is based on data up to 2012 so it’s worth noting that this data is now 5 years old (3 years for the project prevalence figure), so even these figures may still be conservative.  The document, which was published in 2017 can be found here: Click here.  A short summary follows:

In this population-based study that included 64 971 patients with neuroendocrine tumors, age-adjusted incidence rates increased 6.4-fold between 1973 and 2012, mostly for early stage tumors.  Survival for all neuroendocrine tumors has improved, especially for distant stage gastrointestinal and pancreatic neuroendocrine tumors.

Of the 64 971 cases of NETs, 34 233 (52.7%) were women. The age-adjusted incidence rate increased 6.4-fold from 1973 (1.09 per 100 000) to 2012 (6.98 per 100 000). This increase occurred across all sites, stages, and grades. In the SEER 18 registry grouping (2000-2012), the highest incidence rates were 1.49 per 100 000 in the lung, 3.56 per 100 000 in gastroenteropancreatic sites, and 0.84 per 100 000 in NETs with an unknown primary site. The estimated 20-year limited-duration prevalence of NETs in the United States on January 1, 2014, was 171 321

Conclusion: The incidence and prevalence of NETs have continued to rise in the United States, owing to the increased diagnosis of early-stage disease and possibly stage migration. The survival of patients with NETs has improved, and this improvement has been greater for those with distant gastrointestinal NETs and, in particular, distant pancreatic NETs.

Combine that with a revised annual incidence rate of 23,000 and the very well known fact that NETs is a highly prevalent disease, it must be mathematically impossible for the figure not to be above the USA rare threshold of 200,000 in 2017.  As you can see from the graph below, the incidence rate for NETs continues to outstrip the incidence rate for all malignant neoplasms (another word for tumour).  Amazingly, the report authors even state “…….. it is likely that we have underestimated their true incidence and prevalence”.

not rare yao netrf

incidence 2012 jama
NET Cancer diagnoses continues to outstrip all other cancer diagnoses

The NET Research Foundation published an amazing infographic which summarises the output of the SEER 2012 study (although it does omit the prevalence figure ‘as at’ date).  See it below and you can read the accompanying text here.

dasari-infographic-2
Graphic from the NET Research Foundation – https://netrf.org/study-shows-rising-rates-of-net-incidence-prevalence-and-survival/

Let’s do the Math

Neuroendocrine Cancer is not only the fastest growing cancer in incidence terms but as a group of cancers, given the mounting epidemiological evidence, it can no longer be rare as a grouping of cancers.  Neuroendocrine disease IS NOT RARE.

For example, if you roughly extrapolate the US SEER data graph above to 2017 and recalculate the prevalence rate based on 23 000 per year from the 2014 figure of 171 321.  Unfortunately, some people will have passed, but it’s well documented as a highly prevalent cancer and therefore more people live. The prevalence of neuroendocrine tumors in USA was higher than the combined estimated prevalence of esophageal cancer (n = 36,857), gastric adenocarcinoma (n = 79,843) and pancreatic adenocarcinoma (n = 49,620) in 2013. In fact, one of the conclusions of the 2012 SEER report is that we are living longer with NETs. This is in line with many other cancers due to improved diagnostic and treatment regimes.  Cleary more work still needs doing.

Dr Kunz has done the math
hendifar not rare
Dr Hendifar has done the math
not rare yao netrf
Dr Yao has done the math

simron singh nets not rare
Dr Singh has done the math

strosberg not rare
Dr Strosberg has done the math

The Invisible NET Patient Population

The heading of this section is my name for those who have not yet been diagnosed with NETs but are walking around having been either misdiagnosed, diagnosed with another cancer in the same part of the anatomy, living and putting up with the symptoms whilst the tumours grow.  To add to this part of the underdiagnoses of NETs 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 had 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

Go figure

Whilst reporting has been improved, it is most likely still not 100% accurate. Therefore, even the figures above may be understated due to an incorrect cause of death reporting and incorrect diagnosis/recording of the wrong cancers (e.g. pNETs recorded as Pancreatic Cancer, Lung NETs recorded as Lung Cancer, etc).  This is certainly still happening in UK and I suspect in most other countries. Add to that the regular reports of Neuroendocrine Tumours being found during autopsies and you have the potential for an even further unrecorded increase had these been found prior to death. In fact, according to SEER 2012, the true incidence and prevalence is most likely underestimated. In fact here is a statement straight from the horse’s mouth:

SEER 2012 Underestimated
more math

The issue is also complicated by the method used in USA for naming a disease ‘rare’. Rather than use incidence rates, the USA uses the number of people living with the disease at any one time (i.e. essentially the prevalence). This is currently 200,000 as a threshold – anything below that is considered rare.  It seems mathematically impossible for NETs to be less than 200,000 given the data provided above.

Eric Liu Not Rare

When I first started researching NETs back in 2010, the US figure (which varies from source to source) was around 125-150,000.  Why are people quoting figures less than this in 2017 when the 2014 figure has now been confirmed above? There also seems to be a selective omission of the new US incidence rate of 7/100,000.

You will also see that Dana Farber is estimating more than 200,000 people are as yet undiagnosed.  Even if that were 50% accurate, it would put the current prevalence figure in US over 300,000.

Let’s cut to the chase – NETs are not rare, they are just less common

Are we shouting loud enough about this?  I don’t think so.  ‘Rare’ is very frequently used within the NET community almost to the point of being a status symbol. Based on these figures, this looks like an outdated approach along with its associated icons.  The evidence above is so compelling that saying the group of cancers officially called Neuroendocrine Neoplasms is rare is starting to sound like fake news.

“A neoplasm on the rise.  More prevalent than you may think.  Incidence increased dramatically during past 3 decades” (Novartis)

“it’s less rare than we used to think. It’s more malignant than we previously thought” (Dr Richard Warner)

“…..it is one of the most rapidly increasing cancers in the U.S. There has been a 500-percent increase in the last 30 years” (Dr Edward Wolin)

“Estimated more than 200,000 undiagnosed cases in the US” (Dana Farber)

“I actually think NETs are not a rare cancer” (Dr James Yao)

“NETS will no longer be rare” (UKINETS 2017 one of the opening slides)

“NETs are no longer rare” (Dr Andrew Hendifar)

“…..when you think of prevalence, NETs are actually quite common” (Dr Jonathan Strosberg)

“One study showed that the number of people diagnosed has risen 50% over the last decade and unfortunately, I worry that is an underestimate” (Dr Eric Liu)

“Neuroendocrine Cancer – NETs are not rare, just less common.  We need a new paradigm” (Ronny Allan since 2015)

You may also wish to check out my article “The Invisible NET Patient Population” where this is explored further.