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Neuroendocrine Tumours – not as rare as you think

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Kunz Neuroendocrine tumors were once considered rare

Background

Although initially considered rare tumours, the most recent data indicates that 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 commonest gastrointestinal malignancy after colorectal cancer.

In fact, the graph of the SEER database from 2004 indicated that the rate of incidence increase was faster than any other cancer on the planet, the rise mainly attributed to lung, small intestine, and rectal NETs.  However, since the World Health Organisation’s revised classification of Neuroendocrine Neoplasms in 2010, there would be a significant increase if this data exercise was run again. This is due to the abandonment of the division between benign and malignant NETs following the 2010 declaration that all NETs now have malignant potential and are graded accordingly.  The 2004 SEER data compiled did not take into account 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”.

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.

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 ‘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:

dana-farber-200000

US SEER – The Trigger and Turning Point

In the largest study of its kind, 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. 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 by 2017. 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’).

This is an astonishing set of statistics – particularly as they are based on data which was 12 years old. However, there is now new data 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]

Meanwhile in UK …….

The latest figures from Public Health England (PHE) indicate the incidence of NETs has risen to 8/100,000 (i.e. not rare) using the latest International Classification of Diseases for Oncology (ICD-O) methodology version 3 – ICD-O-3.  That means a new NET diagnosis every 2 hours. You can see a summary of the report here which is based on 8,726 cases:   NEW:  Public Health England release new incidence data for Neuroendocrine Cancer

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 a study based on data up to 2012 (worth noting that this data is now 5 years old (3 years old for the project prevalence figure), so these figures may be conservative.  The document, which is only recently published, 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 seems mathematically impossible for the figure not to be above the 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”.

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.  See it below and you can read the accompanying text here.

Do the Math

So it seems that Neuroendocrine Cancer is not only the fastest growing cancer in incidence terms but as a group of cancers, it is no longer rare in statistical terms.  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 line with many other cancers due to improved diagnostic and treatment regimes.  Cleary more work needs doing though.

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.

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.

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? 

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 our community almost to the point of being a status symbol (not sure why – to be rare is to be ignored).  Based on these figures, this looks like an outdated approach along with its associated icons. Statistically, rare cancers don’t normally do well in comparison to the more common types and they certainly don’t attract the same resources and research.

“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)

“Neuroendocrine Cancer – it’s not rare, it’s less common.  We need a new paradigm” (Ronny Allan)

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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27 Comments

  1. Ronny Allan says:

    No proper scientific evidence that it cures any cancer.

    Like

  2. James Patterson says:

    Is there any of record of net cancer being cured with cannabis or does it help

    Liked by 1 person

  3. Coral says:

    I have always maintained that I do not think NETs are rare, but rarely diagnosed…otherwise, 90% plus of us wouldn’t be diagnosed at the stage 4 level or misdiagnosed for 6 to 10 years. And when we see the numbers of new cases each year around the world, I cannot believe that this increase is due to newness of disease, but rather newly diagnosed.

    When patients start asking questions, daring to challenge, learn to advocate for themselves, and stop thinking that someone else has all the answers for them, I think we will start seeing differences in numbers. It starts with educating self, and then others. Awareness is always key.

    Like

  4. PJWatson says:

    This is a tremendously important post, Ronnie (thank you, thank you). Raising awareness of NETs–and thereby improving research, funding, detection, and treatment prospects–is far more effectively done by highlighting their fast-rising incidence and prevalence than by continuing to (mis-)characterize NETs as rare.
    I hope your hard work leads to a more “common” way of thinking about NETs!

    Liked by 1 person

  5. Jill says:

    This is a tremendously important post, Ronnie–thank you, thank you. To really help raise awareness of NETs (thereby improving research, funding, detection and treatment opportunities) it is far more helpful to highlight the fast-rising incidence and prevalence of NETs than to continue (mis-)characterizing them as “rare.”

    I hope your hard work inspires a more “common” way of thinking about NETs!

    Liked by 2 people

  6. […] the reason that so many people have such bad experiences is that NETs is a rare disease (although not as rare as once thought), and even most medical professionals have little to no experience with it. Often their information […]

    Like

  7. Cherie says:

    Probably a dumb question, but does the 100,000 refer to cancer cases or population?

    Liked by 1 person

    • ronnyallan says:

      A cancer incidence rate is the number of new cancers of a specific site/type occurring in a specified population during a year, usually expressed as the number of cancers per 100,000 population. That is, Incidence rate = (New cancers / Population) × 100,000

      So for example if the incidence rate for ‘Cancer Type A’ is 10 / 100,000 and the population of the country is 10 million, that means there would be 1000 people diagnosed each year with ‘Cancer Type A’.

      Great question Cherie and not dumb at all (on the basis I had to think about it!)

      Like

  8. eladatacoach says:

    I think it is extremely important that you’ve identified the earlier and better awareness and diagnostic techniques as, possibly, the greatest factor in the increase in Incidence, Ronny. Particularly as it correlates with the decrease in metastasis. I am so very grateful that so many more community doctors, oncologists, and other specialists are learning about, and studying, NET cancers. That is our greatest tool to help others who, too often, are still misdiagnosed for many years. I also believe this correlation is critically important to dispelling the fear mongers who want to blame “big pharma” and the medical profession in general for “causing” or “not curing” cancer for their benefit and profit. I have yet to meet a medical professional or pharmaceutical researcher who is not concerned about, and focused on, curing the Big C!

    Liked by 1 person

  9. I agree with Emma that in my experience it is not rare but still rarely diagnosed. I suspect because Doctor’s are associating carcinoid with carcinoid syndrome which does not always appear, especially in earlier stages. After many years of abdominal pain with no apparent cause, my brother was diagnosed with midgut carcinoid with mets to liver in 2005 and didn’t experience carcinoid syndrome until his liver had a tumor volume of 90%. Another friend went to ER repeatedly for vomiting but was never diagnosed until they determined that he had liver tumors that had metasthesized from the lung. He was treated for lung carcinoma and passed away 6 months later. His obituary stated death by lung cancer but I had spoken to his wife who confirmed it was neuroendocrine. Another friend had digestive issues for a long time and was assured by her GI doctor that she did not have pancreatic cancer. She was only diagnosed when the P-NET had engulfed her biliary ducts and hepatic vein causing death by bleeding 3 months later. The death certificate stated “pancreatic cancer” as cause of death. Ironically her husband had worked for Steve Jobs. My point is if I am aware of 4 cases among my family and circle of friends, how can it be rare?

    Liked by 1 person

    • ronnyallan says:

      I cringe when I think about the number of people who may have died and had their death recorded as something else. Additionally, when people with a Lung, Pancreatic or Small Intestine NET, have had their illness recorded as Lung Cancer, Pancreatic Cancer and Bowel Cancer – not to mention all the other areas of the anatomy. I have a plan to blog about Carcinoid Syndrome and Carcinoid Cancer – particulary about how they are sometimes (incorrectly) used interchangeably.

      Thanks for the comment – amazing story!

      Like

  10. Beth says:

    Nice post Ronny. I think one of the major reasons for the increase in prevalence of the disease was the introduction of somatostatin analogues (Sandostatin LAR and octreotide) in the mid-1990’s which increased the life expectancy of NET patients dramatically.

    Liked by 1 person

  11. Emma B says:

    In my own experience it certainly doesn’t seem rare, my husband was diagnosed in December, a colleague two desks over realised that it was the same rare type as her grandma has been diagnosed with around two years ago, then another colleague said her sister has it too, although hers is pancreatic. It has been a great support having people closely affected within my immediate work environment, comparing experiences of treatment, especially as the other two are being dealt with in London, whilst my husband has opted for the Birmingham Centre of Excellence. The team at Birmingham have recently confirmed he has one metastatic liver tumour which is 2.2mm and are planning radiofrequency ablation to remove it.

    Liked by 1 person

  12. Ronnie these stats show that NETs are increasing but malignancy decreasing. Therefore NET cancer is decreasing. This is good news because it means tumours are being caught early before they metastasise. That’s one interpretation anyway, if you follow that train of logic Net Cancer is still rare.

    Liked by 1 person

    • ronnyallan says:

      I think I see where you’re going with that but I do not believe the stats have taken malignant vs benign (which is itself a moot point) into account. I think certain types of NET are rare (i.e. anything other than Lung, Small Intestine or Rectal) but our group of cancers counts as one cancer and therefore that is what statistics measure (similar situation to different types of breast cancer for example). I believe there is a lot of merit in not being called rare as I alluded to in the blog. Thanks for taking the time to comment Linda – hope you are well?

      Like

      • Ronnie I do agree that its not as rare as we are all led to believe, mainly down to under diagnosis. I do think however if the researchers cant get their terms right then the research is mince. In this case I suspect they have got it right otherwise why make the distinction. Do you have a link to the full research paper? It is important to get this right.

        Liked by 1 person

      • ronnyallan says:

        the research is based on USA but as you’ve seen from the blog, Norway and more recently Canada confirm big rises. The links are in the blog marked [1], [2] etc. The USA is very good at recording due to insurance company requirements (i.e. they don’t get paid unless the treatment/diagnosis matches the ICDs). A UK consultant told me last week, the NHS is not very good and one should multiply whatever figure you’ve got for NETs by 5. I suspect because NHS/NICE take an anatomy based approach to diagnosis and I suspect if they get recorded at all, there will be many incorrect recordings, i.e. lung NETs as lung cancer etc (you only need to look at the recently updated NICE guidelines on Cancer diagnosis to see it’s a total disaster for NETs).

        Like

      • Ronnie I think I see what you mean now. As a non medical person it beggars belief that in the uk we have no data base for these tumours. Actually we have no real idea what the real incidence rate is because its not recorded properly. Some of these studies don’t even take into account the full range of NETs but give no indication of why not possibly because metastatic disease is so rare in these net types? What a mess. More research needed!

        Liked by 1 person

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