Epidemiology – a patient’s view

Most people seem to only think of Carcinoid Syndrome when they discuss NETs. And what is this term I see called “Malignant carcinoid syndrome”?  When you study many websites, it often appears to be the only syndrome of concern, inferring that all NET patients will potentially get carcinoid syndrome and/or that all symptoms of NETs are caused by carcinoid syndrome. However, this is way off the mark, particularly as other NET syndromes and other illnesses can present with the two cardinal symptoms of dry flushing and/or diarrhea.  Judging by the amount of feedback and what patients are being told and then repeat in my patient group, some doctors also seem to be oblivious to this fact.  For example, symptomatic pancreatic NETs need to be tested for more than just carcinoid syndrome! (see more about this below in section “It’s not all about carcinoid syndrome”.

The other inference on many websites is that a syndrome is normal when in fact not everyone will have a ‘syndrome’ in addition to their tumours, i.e. most NETs are non-functional. In fact, in certain types and all stages of NET, some NETs are rarely functional but others more so.  

Statistics on (so called) carcinoid syndrome are lacking and where there are statistics, they tend to be single centre based surveys, ergo, they can vary widely from source to source. However, it is estimated that around a third of all ‘midgut’ patients (predominatey small intestine NETs) will present with metastatic disease and up to a third of those will exhibit Carcinoid Syndrome indicating their tumours are ‘functional’ (secreting excess hormones, predominately serotonin). It follows that Carcinoid Syndrome itself is not that common. The perception is different in patient online groups because those with advanced and ‘syndromic’ cancers tend to join groups looking for support. Consquently there is an overabundance of syndromic patients in NET groups vs the general NET population. Patients and caregivers/carers in patient groups need to factor that in.  Also I do note from anecdotal statements in my own group that many doctors give the “easy” explanation of “carcinoid syndrome” to explain symptoms even in the absence of elevated hormones to match (and often without testing for other syndromes known to be related to the patient’s primary) e.g. Flushing and/or diarrhea can be found in other NET hormonal syndromes and the differentials are wide. 

Clearly over the years, the number of carcinoid syndrome cases have been reduced, possibly due to an increase in early stage diagnosis, introduction of somatostatin analogues and the production of more robust guidelines for diagnosis and surveillance.

In fact when you look wider and at newer studies, the figure of around 20% appears to be the most accurate. 

The prevalence of carcinoid syndrome within all NEN was reported as between 18% and 72% based on older series. More recent European data show a prevalence of carcinoid syndrome in 25% of 837 patients with GEP-NENs and 20% of all 1263 NEN patients. ³  A recent article by Halperin et al. analysed the SEER database in the USA, and this demonstrated that 19% of patients with neuroendocrine neoplasm had carcinoid syndrome, giving an overall incidence of carcinoid syndrome of 1 : 100 000 population”. ⁴  The difficulities of getting an accurate figure can be explained by the methods the Halperin (et al) study used work their figure out. However, I like that they pragmatically did not include pancreatic NETs supporting my observations in this section. 

Of course these figures will vary between countries/regions.  The heterogeneity of NETs has resulted in many different rates of prevalence and incidence, determined by the predominant site of the tumour, the vulnerable population, ethnic differences, and lifestyle.  e.g.  The distribution of GEP NETs differs regionally as in North America small intestinal and rectal NETs are most prevalent, in Asia rectal and pancreatic NETs are most prevalent, and in Europe small intestinal and pancreatic NETs are most prevalent. ⁵

These varied aspects demonstrate the need for national and regional databases based on the right diagnosis (i.e. carcinoid syndrome only when it is carcinoid syndrome), the use of common terms. Looking wider, there may also be differences in local/regional diagnostic efficacy and/or availability of advanced diagnostic testing capability.  

It does not help that many sites online appear to be stuck in the 1980s.  In their defence, up to date figures on carcinoid syndrome are lacking and difficult to produce (something accepted in some recent references I used in my research). I am convinced some of this difficulty is because of what I said above.  Not all, but some.

It’s not all about carcinoid syndrome

As above, most people seem to only think of Carcinoid Syndrome but there are in actual fact, several associated syndromes depending on the anatomical location, the type of NET, and the predominant hormone being oversecreted causing the syndrome. This is a highly prevalent assumption in NET patient forums where many assume they have so called “carcinoid syndrome” or have been told “carcinoid syndrome” by their doctor. I always raise an eyebrow when I look at the NET type, stage of the disease and primary location of some of these claims. Take Pancreatic NETs as example, they were never historically called “carcinoid tumours“ and they do not typically cause carcinoid syndrome. It’s not impossible to have a predominately serotonin producing tumour sufficient to cause carcinoid syndrome in the pancreas but it is highly unusual, one pancreatic NET study puts it at 0.8%.

In summary, and this is my personal opinion, the epidemiology of carcinoid syndrome will remain difficult to calculate unless the differentials for these symptoms have been corroborated to pinpoint causal factors; and as I said above, national and regional databases need to be based on the right diagnosis (not the assumed) and the use of common terms.  Consequently I believe the figures are overstated and have been for years.  Also, as I alluded to above, until websites talking about Neuroendocrine Tumours/Neoplasms are updated from 1980 thinking to 2020 relevance, the perception that carcinoid syndrome is more common than it actually is, will continue to confuse.

I also wish doctors of (say) pancreatic NET patients would spend some time checking the known pancreatic NET hormone levels rather than just defaulting to so called carcinoid syndrome. All of this is most likely related to the lingering use of the outdated misnomer “Carcinoid“.  It helps when seeing a NET Specialist team who should hopefully understand these things.