Carcinoid syndrome (CS) is the most frequent hormonal complication accompanying neuroendocrine neoplasms (NENs) and is defined by chronic diarrhoea and/or flushing in the presence of systemic elevated levels of serotonin or its metabolite 5-hydroxyindolacetic acid (5-HIAA). Importantly, other causes of these symptoms should be considered and investigated depending on the clinical presentation. CS is predominantly encountered in patients with well-differentiated NENs (neuroendocrine tumours, NETs) of intestinal origin, followed by lung NETs, and only in a minority of patients with pancreatic, ovarian, thymic, or unknown origin NETs. The main symptoms defining CS are skin flushing, secretory diarrhoea, bronchospasm, or abdominal pain (in some cases of advanced intestinal NETs) in the presence of systemically elevated levels of serotonin and/or other biologically active amines and peptides. Patients with CS suffer from an impaired quality of life (QoL), which is lower when compared to patients without CS or other types of cancer.1
In severe cases it is also related to two major (although uncommon) complications which are not included in this spotlight but those with diagnosed carcinoid syndrome should be aware:
….. and also related but science is lacking confirmation – Mesenteric and Retroperiotoneal Fibrosis
As above, in patients with Neuroendocrine Tumours (NET), it predominately affects small intestine NETs, particularly in advanced cases with liver metastases but other scenarios are possible (see Pathophysiology below).
Carcinoid syndrome occurs when biologically active amines and peptides enter the systemic circulation escaping the first-pass metabolism of the liver. Normally, these bioactive products are inactivated by the liver.
However, in cases of neuroendocrine tumours with liver metastasis, either these bioactive products are directly released into the systemic circulation, or they escape inactivation due to deranged liver function.2
e.g. Rarely, carcinoid syndrome can occur without liver metastasis in conditions, mainly:
a. A primary midgut tumor with extensive retroperitoneal nodal metastases as lymphatic drainage of retroperitoneal lymph nodes goes to the thoracic duct.
b. A bronchial NET, where it’s sometimes possible for bioactive amines to be released directly into the systemic circulation.
c. Secreted substances can also bypass the liver and reach the systemic circulation from ovarian carcinoids, as ovarian venous drainage can bypass the portal circulation.
Despite a lack of evidence to back this up, some sites report that NETs release about 40 different types of biologically active amines and peptides. The most common related to carcinoid syndrome are serotonin, histamine*, tachykinins, kallikrein*, and prostaglandins*. The majority of midgut symptoms are said to be due to serotonin which is a product of tryptophan metabolism.2 Thus why only serotonin and its metabolite 5-hydroxy indoleacetic acid (5-HIAA) is used for diagnostic and surveillance. Usually, only 1% of dietary tryptophan is converted into serotonin. However, in a patient with carcinoid syndrome, up to 70% of tryptophan can be converted into serotonin. Serotonin undergoes oxidative reaction and leads to the formation of 5-HIAA by aldehyde dehydrogenase, which subsequently is eliminated into the urine.2
Serotonin causes increased motility and secretion of gastrointestinal tract resulting in diarrhea. As most of the body’s tryptophan is diverted to serotonin formation pathway by neuroendocrine tumours, it can sometimes lead to a deficiency of tryptophan which is needed for synthesis of niacin. Subsequently, in extreme cases, deficiency of niacin occurs causing Pellagra. Prostaglandins* also mediate increased intestinal motility and fluid secretion in GI tract causing diarrhea.2
Neuroendocrine tumours of foregut and lungs do not contain the enzyme aromatic L-amino acid decarboxylase which converts 5-hydroxytryptophan to serotonin. Thus, lungs and foregut neuroendocrine tumours do not normally produce serotonin. Consequently, in these anatomical areas, the tumour’s defect in the aromatic amino acid decarboxylase (AAAD) enzyme prevents the conversion of 5-hydroxytryptophan (5-HTP) to serotonin (5-HT), leading to the secretion of 5-HTP instead. Often known as ‘atypical carcinoid syndrome’.
Hindgut neuroendocrine tumours usually do not normally produce any bioactive hormone.
Pulmonary neuroendocrine tumors are said to mainly produce histamine*, which can cause atypical flushing and pruritus. Tachykinins (substance p, neurokinin A, neuropeptide k) are also responsible for causing flushing due to their vasodilatory effect. 2
* see section below entitled “Which hormones are truly involved in Carcinoid Syndrome?”
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 (predominately 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. Consequently 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 difficulties 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.
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.
Carcinoid syndrome is a by-product of NETs oversecreting the offending hormones, predominately serotonin. Prior to diagnosis of the NET, these symptoms may confound primary and secondary care physicians leading to delays in arriving at the right diagnosis. However, for most, the tumours will be found via imaging or endoscopic devices, leading to tissue sampling and subsequent diagnosis. As part of this process (before or after diagnosis), testing for biochemical markers could include as a minimum:
5-HIAA is the initial diagnostic test. The 5-HIAA is the end product of serotonin metabolism. Most locations are using the 24-hour urinary version but the plasma version is growing in use. Read more by clicking here.
Chromogranin A is an indicator of tumour bulk but while sensitive, it has poor specificity. However, for many it will provide indicative evidence if none of the contraindications apply. It’s not a diaganosis of Carcinoid Syndrome per se but read more by clicking here.
Blood serotonin is usually not recommended as the specificity of this test is not reliable.
This is very complicated and I’m going to leave the detail to the experts. There are many variables involved including stage, although for most with carcinioid syndrome it will be later stages (predominately metastatic midgut and less commonly with lung NETs).
Surgery can play a large part normally by reducing hormonal oversecretion, i.e. reducing tumour bulk (debulking). Not always a correlation though.
First line tends to be somatostatin analogues (SSA) which act as a hormonal supressor via somatostatin receptor positive cells, also having a mild anti-tumour effect over time. For those whose carciniod syndrome diarreah is not adequalty contolled by SSA, Xermelo is a known inhibitor of sertonin production and therefore reducing the diarrhea caused by carciniod syndrome. Xermelo is normally prescribed together with a SSA.
Other targeted therapies e.g. Peptide Receptor Radionuclide Therapy (PRRT)/Radiologiand Therapy (RLT) and where applcable liver directed theapy can play their part in influencing hormonal oversecretions. Again, not always a correlation though.
In this section I also wanted to alert you to some useful information in regards surgery. Surgery for Small Intestine (Small Bowel) is not normal bowel surgery. It can be advantagoeus to have it done by surgeons experienced in carrying out this type of operation. Click here to read some useful expert guidance on things to look for.
The Guidelines for treating Carcinoid Syndrome are given below.
We all know about the involvement of Serotonin and we have seen others mentioned but there is normally no set list and various sources of information seem to differ about what does what. What is the evidence?
This study from the Netherlands suggest some hormones may not be involved in carcinoid syndrome as the evidence is insufficient. To quote the top NET Specialist from one of the world’s top NET Centres of Excellence “Our review shows that the evidence for the other mediators is insufficient to reliably appoint them as mediators for CS. Definitely more research, using modern assays, is needed.”
Merijn C F Mulders, Wouter W de Herder, Johannes Hofland, What is the carcinoid syndrome? A critical appraisal of its proposed mediators, Endocrine Reviews, 2023; bnad035, https://doi.org/10.1210/endrev/bnad035
Information within guidelines has been scant but this is improving. The latest guidelines for carcinoid syndrome (and carcinoid heart disease) can be found by clicking here or Reference 1 below. Reference 6 mentions this it in section NET-13.
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.
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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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