If you read any authoritative source on this cancer, it will normally begin with “Neuroendocrine Neoplasms (NENs) are a group of heterogeneous tumours ………….”. The term heterogeneous means diverse in character or content; or a structure with dissimilar components or elements. This is not surprising as these tumours are found in Neuroendocrine cells throughout the vast majority of the human anatomy.
And yet, when you look at many hospital/healthcare sites, advocate organisation sites, and cancer information sources not maintained by Neuroendocrine Cancer scientists or specialists, you might start to think there is just one big type of NET and only one syndrome. This shows a total lack of understanding (or effort) to provide the right detail. It also is connected to the lingering use of the term Carcinoid.
However, while I applaud national and international NET foundations for providing GP (PCP) with symptom lists, some are part of the problem by ignoring heterogeneity. i.e. they should provide all the symptoms related to each primary type instead of lumping just the carcinoid syndrome symptoms inferring involving with all NETs. Only 10% of NETs are related to carcinoid syndrome. What about the other 90% ???
Too many people make blanket statements about Neuroendocrine Cancer which are misleading, e.g.
……. I could go on.
In my opinion, all inaccurate or misguided. Why the confusion?
1. Every thinks every NET is extremely rare when as a group it is not and it is certainly not when you look at prevalence. If we keep telling people it’s rare, they won’t write about it, they won’t update their websites about it, they won’t look for it.
2. Many of these myths are connected to the incorrect use of the term Carcinoid to describe all types of this cancer. The term carcinoid is dead, get used to it.
3. A lack of context in patient advocate foundations awareness campaigns and robust moderation in patient groups, in some cases, unchecked over a period of years. Many other healthcare sites and professionals take their lead from this unchecked information. This has lead to almost mythical belief and distortion of facts. Patients are inadvertently sharing compete dross.
4. A lack of appreciation of the heterogenous nature of Neuroendocrine Neoplasms.
In truth, and at the highest level, the most up-to-date classification system allows for two fundamentally different groups of NENs: well-differentiated, low-proliferating NENs, called neuroendocrine tumours (NETs), and poorly differentiated, highly proliferating NENs, called small- or large-cell neuroendocrine carcinomas (NECs).
Even within a single grade, there can be huge differences, e.g. in Grade 3, the differentiation becomes crucial and may heavily influence therapy and prognosis.
I must also mention the possibility of further shades of grey by introducing Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) – read more here.
Another striking difference is in the primary locations. Well-differentiated NENs are more common in the pituitary, thyroid, parathyroid, thymus, stomach, small bowel, appendix, rectum, and pancreas, while poorly differentiated NENs are relatively more common in the lung, esophagus, colon, urogenital organs, and skin. Different primaries have different pathophysiology’s, some metastasise a lot, others don’t. So many different shades of grey.
Within that, the epidemiological significance of the stage of each tumour can produce many shades, e.g. statistics over decades show that some tumour types will rarely or infrequently metastasise beyond the local area, while other types are prone to metastases, with many presenting at Stage 4.
In the group of the Gastroenteropancreatic NENs (GEP NENs), there are subtle differences between small intestine (particularly ileal), appendiceal, and pancreatic NETs. Ileal and appendiceal NETs, though sharing the production of serotonin, differ fundamentally in their clinical course, which is largely indolent (tumours often behaving in a benign fashion) in appendiceal NETs but usually malignant in ileal NETs. In contrast, ileal NETs follow a more indolent course than Pancreatic NETs, also differing profoundly in their molecular profile.
Small localised low-grade appendiceal, type 1 gastric NET, and rectal NETs are typically indolent and rarely metastasise. Small, localised tumours are normally excised with curative intent (NET specialist words not mine) and may never bother the person again. Others may need longer surveillance periods.
At stage 4, cancer is said to be incurable but with low-grade well-differentiated NETs, stage 4 is not the red flag it is with other aggressive cancers and while it may be incurable, it is not untreatable. Incurable is not necessarily terminal in indolent (but metastatic) low-grade disease.
I believe that heterogeneity also extends to other areas producing even more shades of grey. Let’s look at syndromes as one major example:
Functional/Non-Functional
When you read the content of the average social media patient group, it’s almost as if everyone has a syndrome and often there is only one syndrome mentioned. Statistics collected over decades are ignored and this issue is exacerbated by flawed statistics emanating from advocate organisations. But in reality, only 10-20% of cases involve carcinoid syndrome (where appropriate) and, in another example, 75-90% of pancreatic NETs are said to be non-functional.
Most cases of functioning tumours are related to the late stages, but the earlier appearance of syndromes remains possible in some NETs, e.g. ovarian. NETs of the foregut and lungs do not contain the enzyme aromatic L-amino acid decarboxylase which converts 5-hydroxytryptophan to serotonin, thus, they do not normally produce serotonin. Most Gastric, Lung and Rectal NETs will not be functional but when they are, it could be a form of atypical carcinoid syndrome likely to be from other dominant hormones rather than serotonin. And it could be a side effect of the tumour growth rather than a syndrome e.g. wheezing caused by an obstruction to the airways is not carcinoid syndrome wheezing. Carcinoid syndrome is highly unusual in a pancreatic NET and doctors and patients should be looking for the known pancreatic syndromes in equal endeavour where a functional/symptomatic pancreatic NET is suspected.
Hindgut NETs usually do not normally produce any bioactive hormone. They are normally unable to convert tryptophan to serotonin and other metabolites and therefore rarely cause carcinoid syndrome even if they metastasise to the liver.
Sorting out the symptoms
When you consider the above, it should not be a surprise to know that different types of NET will produce different symptoms. These symptoms may be from two main sources; side effects of the tumour growth affecting local areas and if the tumour is functional, from the relevant syndrome producing the effect. AND YET when I read authoritative sites written by healthcare professionals, written by advocacy organisations, and also comments made in patient groups, you might end up thinking there is only one syndrome with two symptoms.
For example, flushing. The inference on many sites is that this is caused by so-called carcinoid syndrome, but it is also a potential symptom of Pheochromocytoma/Paraganglioma, Medullary Thyroid Cancer and certain pancreatic NETs (almost always not carcinoid syndrome). Many people claim this is due to elevated serotonin and yet even within carcinoid syndrome cases, it is most likely the case that serotonin is not even the dominant hormone involved.
Similarly, let’s look at diarrhea. In many cases, this will be caused by a myriad of reasons, including some issues not even related to NETs. Even within NETs, the suggestion that it is carcinoid syndrome is very often way off beam, as surgery and other therapies will be related to these issues in many cases. Serotonin is most likely the dominant hormone causing syndrome diarrhea. BUT there are other types of NETs that are not serotonin-secreting that may have diarrhea as a side effect (i.e. not caused by carcinoid syndrome!). Examples include but are not limited to; Medullary Thyroid Cancer, Pheochromocytoma / Paraganglioma, and pancreatic NETs where the malabsorption symptoms of pancreatic exocrine insufficiency (PEI) are often confused with diarrhea. The PEI issue may also affect any patient receiving long-term somatostatin analogues.
Only around 10% are related to genetic or hereditary diseases. This may be higher in certain primary locations or certain hereditary disease groups. Read more here
Future editions of NEN classifications may include molecular profiling for each ‘shade of grey’ supplementing guidelines, not only helping with diagnosis but also providing a more individualised patient guidance on the right treatment and/or surveillance periods. The total number of shades of grey will undoubtedly increase.
I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.
Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional. Some content may be generated by AI which can sometimes be misinterpreted. Please check any references attached.
Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.
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