It’s about Hormones

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. 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.