As it’s Testicular Cancer Awareness Month, I thought I’d share a personal story with you. This is something regarding my own diagnosis and something as yet unpublished. I don’t tend to share some very personal stuff but this is on the boundary of that rule and there are some important messages to be teased out. For those who follow my blog in detail, you will remember the post entitled “Neuroendocrine Cancer – Signs, Suspicions, Symptoms, Syndromes, Side-Effects, Secondary Illnesses, Comorbidities, and Coincidences”. As you can see from the title, I got hooked on a bunch of synonyms (small s) that represent the difficulty in sorting out what can be attributed to Neuroendocrine Tumours (NETs) and what might be something else. You’ll note they all begin with the letter ‘S’ except ‘Comorbidities’ and ‘Coincidences’. These 2 were actually retrospective add-ons to the blog title and there is a potential overlap between both.
Life is full of coincidences and I’m certain this is also the case with issues NET patients have from time to time. There is a high possibility that some things which were going to happen health-wise before NETs came along, will most likely still happen and it can often seem like the NETs have some causal effect. As my friend Dr Eric Liu says ‘Even NET patients get regular illnesses’.
I also suspect the same thing can happen pre-diagnosis and if you’re unlucky, during the diagnostic phase. This sort of event has the potential to confuse an already confusing diagnosis! So here’s a story about my ‘COINCIDENCE’ which eventually turned out to be a ‘COMORBIDITY’.
At the beginning of 2010 (remembering my diagnosis was July that year), I did what all men should regularly do – I checked my ‘chaps’ for lumps. Sometime in January, I got the feeling my left ‘chap’ was bigger than the right and I monitored that for a few days. Eventually, it was patently obvious there was an abnormality. I immediately went to my GP and he diagnosed a hydrocele. Apparently these are quite common with men. He was able to quickly work this out by shining a torch through the offending gonad area and as the light came out the other side, this was confirmation it was excess fluid. He said it might go away on its own but explained there were medical procedures to correct it including fine needle aspiration (not normally a permanent fix) or surgical repair (the most permanent fix). I left it for a few weeks and as time passed, the size of my left ‘chap’ increased. It became really uncomfortable and painful so I asked to be referred to a specialist. Bear in mind at this point, I still didn’t know I had Neuroendocrine Tumours burrowing away inside me for years.
Fast forward 1 month, the hydrocele is not yet sorted and I’m speaking to a specialist having been referred for a low hemoglobin score (the trigger for my NET diagnosis). At this point, I’m convinced there is a connection and amongst the plethora of tests and checks, the specialist also carried out a fine needle aspiration of my left ‘chap’ (I can hear the male audience wincing). The fluid was sent off for testing and subsequently returned negative. My left ‘chap’ was now back to normal (every cloud…..). By the way, the hydrocele returned around 2 months later. I eventually got the date for my hydrocele surgical procedure (hydrocelectomy) but decided to postpone it to sort out another little matter …… Cancer!
I eventually got it repaired in Sep 2011 after 14 months of NET treatment and had no issues since. Now…… I can almost hear the cogs turning …… the testes are an endocrine organ etc. I’ve been through this too and I was still suspicious for a year after diagnosis. However, I’ve been categorically told there is no connection and there is nothing showing on ultrasound, CT scan or Octreoscan. 4.5 years later, I’m happy there was no connection 🙂
However, I did my duty, I checked my chaps, found an issue and fortunately it was nothing too serious. Crap timing though!
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.
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 inUSA”. 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.
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 . 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 inUSA …….”
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. 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]
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. 
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.
A slide from the recent UKINETS 2017 conference indicating an agreement from UK and Ireland NET Specialists.
Meanwhile in New Zealand …….
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”.
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.
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.
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. DOI: 10.1158/1078-0432.CCR-17-3378. 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:
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:
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? 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)