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). This post will not cover Neuroendocrine Carcinoma which by definition is malignant.
Any definition of the word ‘tumour’ will confirm it can either be benign or malignant. However, and while I’m sure there are benign NETs, the key statement to explain any slow growing or indolent NET is that they all have malignant potential – thus why surveillance and follow up is really important. This is the key factor in the changes found in the 2010 Digestive System World Health Organisation (WHO) classification system from the previous ‘flaky’ version. This reinforcement of the malignant potential of all NETs was duplicated in the recent 2017 Endocrine System equivalent, which is now proposed as a classification scheme for all NETs (see below).
Of course we are not helped by the continued use of the term Carcinoid which decodes to ‘Cancer Like’ – that is potentially regressing the work of those specialists who are trying to undo the last 100 years of complacency in the medical world (and not really the type of awareness we need). The word is gradually being erased from NET nomenclature and the recent 2018 proposal by the International Agency for Research on Cancer (IARC) and WHO NET expert consensus panel to ditch it from the remaining versions of out of date WHO classifications (e.g. Pulmonary/Lung, Pituitary, Head & Neck, Genito-urinary, Adrenal and Paraganglia, Skin), is the final nail in the coffin for Carcinoid. RIP Carcinoid. This also supports our awareness issues with the media reporting the wrong cancer types based on anatomy of the primary tumour. Dear Doctors, Patient Advocates and Patients ….. please stop using the word!
I have lost count of the stories from Neuroendocrine Cancer patients who have been told their tumour was benign but then returned with incurable and metastatic cancer sometime downstream. Clearly there are doctors who do not understand NETs and/or are not aware of the changes in WHO classification schemes since 2010. Sure, some will prove to be ‘benign’ in nature and may not cause many issues but any Ki-67 below 3% is a formal grade of Neuroendocrine Neoplasm. I accept that it’s currently difficult to work out which cases will turn more aggressive and when, thus why surveillance and follow up are really important and also why patients should be seeing doctors who understand NETs. Worth also noting that many slow growing and indolent tumors can still often produce troublesome NET syndromes.
I’ve even heard one patient story where it was claimed a doctor called a metastatic NET case benign! Any definition of ‘benign’ on any respectable cancer site, will include the statement that they do not spread to other parts of the body. The NET Patient world is full of slow growing Grade 1 Stage 4 patients – by definition, they’re all malignant.
Read more detail in these articles as these issues are inextricably linked.
I’m sure there are scenarios in all cancers where tumours can be benign and will never harm the person but if a Doctor says you have a Neuroendocrine Tumour and not to worry because it’s benign, ask questions. Start with “how do you know it will never turn malignant” and “what will be done going forward to check”.
Thanks for listening
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These are my top performing posts for 2017 – comprising one eighth of my entire hits for the year. My blog hits for 2017 almost reached a quarter of a million, double that of 2016 which was double that of 2015. A chunk of these figures can be attributed to most of these articles. Please share to maintain the momentum.
Top 6 posts for 2017 (Click on each article title to read)
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:
2. From Dana Farber (Kulke, Chan):
“Estimated more than 200,000 undiagnosed cases in the US” – this slide here:
…. 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. 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 has ever thought. There’s a summary article here which I suggest you read fully. The rather explosive extract is as follows:
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.
One of the great things about learning is that it never ends 🙂 I came across this piece of information about how chemotherapy was invented. I had no idea. It began as a deadly cloud but it eventually ended up as a silver lining for certain cancer patients. It all began with the development of mustard gas and I’m sure we’ve all seen the awful pictures of solders leading each other from the battlefield having been affected by this ‘deadly cloud‘. Let’s hope we never have to witness that again. This weapon was first used 100 years ago this week (note: blog published in Apr 2015) but out of the horror came a ‘silver lining‘ – the idea behind what is now called chemotherapy.
However, the development didn’t really begin until the second world war when two doctors from Yale University (Louis Goodman and Alfred Gilman), conducted animal and then human trials. Then in 1948, UK scientist Professor Alexander Haddow published a ground breaking piece of research in the journal Nature, showing exactly which bits of the nitrogen mustard molecule were needed to kill cancer cells. Perhaps more importantly, he also found out how to make the chemical less toxic, but with more potent cancer-killing activity. So mustard gas went from the very real battleground of the WWI trenches into the frontline of cancer treatment where it still is today.
One of the unusual aspects of Neuroendocrine Cancer is that chemotherapy is not normally considered as a ‘standard’ treatment unlike many other cancers. The exception is high grade (Grade 3) where it is often a first and/or second line therapy. Poorly differentiated Neuroendocrine disease is normally labelled as Neuroendocrine Carcinoma (NEC) but worth pointing out there is now a Grade 3 well differentiated classification known as a ‘Grade 3 NET’ rather than Grade 3 NEC. Depending on Ki67 score, there could be differing treatment options for Grade 3 NET and Grade 3 NEC. Read more in my article Staging and Grading.
The type of chemo or the combination of different treatments will often depend on the tumour type and anatomical location involved but may include (but not limited to): Capecitabine (Xeloda), Temozolomide (Temodal), Fluorouracil (5-FU), Oxaliplatin (Eloxatin) Cisplatin, Etoposide (Etopophos, Vepesid), Carboplatin, Streptozotocin (Zanosar). Some of these may be given as a combination treatment, e.g. CAPecitabine and TEMozolomide (CAPTEM). many as a combo treatment. There is a useful article explaining the role of Ki-67 in determining optimal chemotherapy in high grade neuroendocrine tumors.
Horses for Courses – Chemo is sometimes used for well differentiated lower grade NETs.
Cytotoxic chemotherapy is often inadequate for treatment of Grade 1 and 2 (well differentiated) Neuroendocrine tumours which have a low proliferation index. Chemotherapy does not appear to like their slow cytokinetic growth. However, it tends to work better on certain parts of the anatomy than others, e.g. pancreatic NETs and Lung NETs. Of interest is a statistic from NET Research Foundation indicating that 23% of patients who were to be prescribed chemo had their treatment changed to a non-chemo option following a Ga68 PET scan. Read more here.
For second line therapy (including for well differentiated NETs where other conventional treatments are not working), chemo may be given. These include (but not limited to) Capecitabine, Temozolomide, Bevacizumab, Xelox, Folfox. There are other specialist chemos for Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).
Capecitabine plus Temozolomide (CAPTEM for short) is fast becoming the standarad chemotherapy treatment when it is required with certain lower grade NETs. Dr Robert Fine says the results of the CAPTEM trial showed “tremendous responses in every neuroendocrine tumor”. The treatment elicited a response rate of 45% and a stable disease rate of 52% including those with certain types of NETs and pituitary tumours – types of neuroendocrine tumour that are notoriously ‘chemoresistant’. You can read more about this here (click here) and you can also listen to Dr Fine enthusiastically talking about this on a short You Tube video clip – (click here). Clearly it is not going to work for all.
Other CAPTEM Resources:
There’s a very interesting report on the use of CAPTEM in NETs – (click here)
In Australia, they’re also using a combo treatment of chemo (CAPTEM) and PRRT – I blogged about this click here.
There’s also a useful surgical technique which includes the use of intra-operative chemo, known as “Chinese Dumplings” – I wrote about this click here.
My Oncologist did mention Chemotherapy on my initial meeting, that was a shock and realisation I had something serious. However, that never transpired but I was once scheduled to have a chemo-embolisation (or TACE, Trans-arterial Chemo Embolisation). Clearly TACE is more targeted than conventional and generally systemic chemotherapy techniques. Perhaps that my Oncologist actually meant. The chemo-embolisation never transpired either (long story).
Chemotherapy vs Targeted Biological Agents and Somatostatin Analogues
I often see people describing Somatostatin Analogues (Lanreotide/Octreotide), Afinitor (Everolimus) and Sutent (Sunitinib) as chemo but that’s isn’t technically correct, and I’ve yet to find a NET Specialist or a NET Specialist Organisation who classifies these drugs as chemo. See my article “Chemo or not Chemo” (click here).
Future of Chemo?
A lot is written about how much longer chemo will be around. It gets a bad press – I suspect mainly due to the side effects. There are suggestions that it will eventually be replaced by Immunotherapyand other treatments downstream. However, immunotherapy is really still in its infancy and there remains a lack of long term data on success rates and side effects. I suspect chemo will be around for a while longer, particularly for cancers where it has a track record of curing according to ASCO. Very recently (June 2018), cancer experts said that chemo will be around for a long time yet – read more here
None of the content of this post should be interpreted as advice or a recommendation for chemotherapy. If in doubt about suitability for any form of chemo, or the type you have been prescribed, patients should seek the advice of their treating doctor or NET specialist.