Neuroendocrine Cancer: At least 50 shades of grey

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If you read any authoritative source on this cancer, it will normally begin with “Neuroendocrine Neoplasms (NENs) are 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. Once again, this is partly related to the lingering use of the term Carcinoid. Even within the community, so many people make blanket statements about Neuroendocrine Cancer which are misleading, e.g.

“they’re all slow growing”,
“they all have carcinoid syndrome”,
“they’re all at risk of (so-called) carcinoid crisis”,
“they all oversecrete serotonin”, 
“they all have hormones thrashing around their bodies”,
“chemo doesn’t work for NETs”,
“they’re all incurable”,
“they’re all rare”,
……. I could go on. 

In my opinion, all untrue and/or misguided, and many of these myths are connected to the incorrect use of the term Carcinoid to describe all types of this cancer; and not helped by a lack of robust moderation in groups. 

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).

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.  So many different shades of grey. 

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. Further 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. 

Many small, localised tumours are excised with curative intent and may never bother the person again.  Others may need longer surveillance periods.  For instance, 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.  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.

It’s not all about stage and grade

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

  • Non-functioning tumours—no specific clinical syndrome is observed
  • Functioning tumours—the tumours’ secretions lead to clinical symptoms

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% 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 such as histamine rather than serotonin.  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 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.

I must also mention the possibility of further shades of grey by introducing Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN)read more here

Summary

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. 

We have a duty to think before we make blanket statements about Neuroendocrine Neoplasms. The only real common feature is the cell type origin, nearly everything else is different. 

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Disclaimer

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 as they are not members of the private group or followers of my sites in any official capacity.  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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