Background

Neuroendocrine Tumours (NETs) can sometimes present with one or more vague symptoms which occasionally results in a lengthy diagnostic phase for some.  Sure, there can be issues with doctor experience and knowledge that can add to the problem. However, some people do present with multiple vague and confusing symptoms and some people have comorbidities that have similar symptoms.  Textbook diagnostics just don’t make sense, sometimes even when the doctor suspects a NET i.e. classic symptoms of ‘something’ but with negative markers for NETs. Clearly, those are extreme cases and just like other complex diseases, diagnoses of NET can be extremely challenging.  Even for an experienced doctor, it can be a difficult jigsaw!

Many types of NET can have associated ‘syndrome‘ i.e. the tumours are ‘functional’ and this is normally (but not always) associated with metastatic disease. At this point, it’s also worthwhile saying that most NETs are ‘silent‘ (non-functional) but particular primary locations may be non-functional for years before any symptoms show and it’s normally only when they metastasize, that these clinical syndromes come to life, this is particularly the case with many metastatic small  intestine NETs. Ironically, the manifestation of the disease with a syndrome can occasionally turn out to be a lifesaver albeit the cancer is normally incurable at this stage, but still treatable.

One of the most common types of NET can often present as a collection of symptoms known as Carcinoid Syndrome and the most common of these is flushing with 84% frequency.  Other symptoms include (but not limited to) diarrhoea, heart palpitations, stomach cramps and general abdominal pain/discomfort, shortness of breath, wheezing.  You can see the scope for confusion and misdiagnosis – it’s a real witch’s brew.

When you look at these general Carcinoid Syndrome symptoms, flushing seems to be the one that stands out as a ‘cardinal sign’ whereas many others are vague and easily confused with common/regular illnesses. That said there are many differential possibilities for the reasons for facial flushing, even within different types of NET!

Guidelines for Flushing

The flushing is reported to be different from most people’s perceptions of a ‘flush’.  The Carcinoid flush is almost always ‘dry’.  To quote Woltering, Vinik, O’Dorisio et al, “…. a good rule of thumb is if the flushing is wet (accompanied by sweating), it is due to a cause other than Carcinoid”.   Dr James Yao, another well-known NET expert also raises this distinction by stating…. “The facial flushing of carcinoid syndrome is usually dry flushing, and not associated with sweating like other kinds of flushing. The flushing is often a symptom that others notice before patients do. They may not feel it themselves.”  That fits because my own personal experience is that I what I now know to be carcinoid syndrome flushing is something I only remember being  around 6 months before I was diagnosed and I had dismissed this as nothing serious but failed to tell a doctor or nurse.
Additionally, from ENETS Guidelines, specific flushing features depend on the primary tumour and four different types of flushing have been described in Carcinoid Syndrome.

• • The first type is the diffuse, erythematous flush, usually affecting the face, neck, and upper chest. This flush is commonly of short duration, lasting from 1 to 5 min, and is related to the debut of Carcinoid Syndrome.
  • The second type is similar to the first type but is violaceous and may last longer, together with facial telangiectasia, being observed in long-term Carcinoid Syndrome from advanced intestinal NETs and is normally not felt by the patients because they have become adapted to the flushing reaction.
  • The third type is prolonged, lasting for hours up to several days, sometimes involving the whole body, being associated with profuse lacrimation, swelling of the salivary glands, hypotension, and facial oedema. It is usually associated with lung NETs.
  • The fourth type (possibly mediated by histamine production), bright red and patchy, may be seen in patients with chronic atrophic gastritis and advanced type 1 gastric NETs. Rarely, type 3 gastric NEN may lead to “atypical carcinoid syndrome” in which flushing can be cherry red, patchy, sharply demarcated, serpiginous, and pruritic.

Not all flushing is carcinoid syndrome

Due to out of date or narrow descriptions of NET hormonal syndromes, many sites still use the misnomer “carcinoid” to represent all NETs, similarly many sites only cover so called “carcinoid syndrome” as if it was the only hormonal syndrome in town.  This is way off beam.

If people read wider and use authoritative sources, it becomes obvious that cutaneous flushing is a common presenting complaint in endocrine and neuroendocrine disorders (i.e. not just in carcinoid syndrome). The issue we have today is that the word “carcinoid” and been used incorrectly for decades by doctors and medical establishments (this continues today in some quarters). Not all hormone-induced flushing is associated with so-called “carcinoid syndrome“, other types of NET syndromes/types can have a flushing symptom, including:

Pheochromocytoma/Paraganglioma – hypertension mainly due to the release of catecholamines and other hormones.  Also causes sweating which may appear to be flushing/hot flash. Flushing in pheo/para is not carcinoid syndrome.

Medullary Thyroid Carcinoma (MTC) – MTC is derived from the neural crest and secretes a variety of biologically active substances including calcitonin, prostaglandins, histamine, substance P, ketacalcin, levodopa, adrenocorticotropic hormone (ACTH), and corticotropin-releasing hormone, which can cause flushing and sweating. Flushing in MTC is not carcinoid syndrome.

Pancreatic NETs – only around 1% of pancreatic NETs are associated with so-called “carcinoid syndrome”.  When you look at that figure in conjunction with feedback in patient groups, it becomes obvious that carcinoid syndrome is being attributed to some of the symptoms of Pancreatic and other NETs incorrectly.  While most pancreatic NETs are non-functional, they can secrete several hormones and peptides leading to functional syndromes, including VIP, gastric inhibitory polypeptide, prostaglandin, insulin, gastrin, glucagon, ACTH, somatostatin, growth hormone–releasing factor (GRF), neurotensin, parathyroid hormone-related peptide, pancreatic polypeptide, and melanocyte-stimulating hormone. Most individuals usually only have symptoms relating to the hormone that is chiefly produced.  Flushing can sometimes be seen in many forms of pancreatic NETs i.e. with a VIPoma around 15-30% will have a flushing symptom as part of the associated syndrome.  Insulinomas can cause flushing during hypoglycemic episodes, Gastrinomas can flush although this is rare. Glucagonoma can present with characteristic necrolytic migratory erythema rash which may be confused for flushing in mild cases.  ………. It does not mean these pancreatic NET patients have so-called carcinoid syndrome.  In fact, only around 1% of Pancreatic NETs have carcinoid syndrome as their functional NET syndrome.  When you consider that most pancreatic NETs are non-functional, that is a small amount.

Cushing’s Syndrome – Endogenous Cushing syndrome is the result of chronic glucocorticoid excess from either an ACTH-secreting pituitary tumour, cortisol-producing adenoma, adrenal hyperplasia, or ectopic production of ACTH and/or CRH from a neuroendocrine tumor. Patients classically present with facial plethora, central body weight gain with limb thinning, glucose intolerance or diabetes with extensive acanthosis nigricans, hypertension, proximal muscle weakness, easy bruising and striae. Flushing is rarely a presenting complaint and is usually subjective, i.e. it’s Cushing’s, not carcinoid syndrome. Facial plethora is consistent and unlike flushing rarely episodic; it is also decreased after surgery, due to a reduction of blood volume perfusion.  Cushing’s syndrome is known to be ectopically related to certain NETs, particularly Thymus, Lung and Pancreatic.  Flushing in Cushing’s is not carcinoid syndrome.

Other misc causes – There are many including but not limited to the following comorbidities: central hypogonadism in men, malignant histiocytoma, neuroblastoma, and ganglioneuroma, from increased production of VIP; TSH-secreting pituitary adenoma causing hyperthyroidism, the use of systemic hormone therapy (estrogen +/− progestogen), selective serotonin reuptake inhibitors, gabapentin, clonidine.  None of these are carcinoid syndrome!

Not all flushing is NET – differential diagnoses for flushing?

The facial flushing associated with NETs should be distinguished from other causes of flushes. The carcinoid syndrome flush is provoked by spicy food, alcohol, and physical and psychological stress, and it is often worse in the morning. Patients with idiopathic flushes usually have a long history of flushing, starting rather early in life and sometimes with a family history without the occurrence of a tumor. Menopausal flushes usually involve the whole body and might be related to the release of calcitonin gene-related peptide (CGRP) with transient vasodilation, a so-called dry flush. Another type of menopausal symptom is the wet flush, which includes epinephrine-induced sweating. Proposed mediators of flushing in menopause are CGRP, histamine, prostaglandins, serotonin, lysyl-bradykinin, and substance P. Estrogen is known to have an impact on the production and release of different signalling substances such as noradrenaline and β-endorphin. Low estrogen levels cause lower β-endorphin activity, which in turn enhances the release of gonadotropin-releasing hormone (GnRH), which gives rise to high luteinizing hormone (LH)levels. Postmenopausal women in whom a true carcinoid syndrome is developing can tell the difference between the two types of flushes. Sometimes patients with medullary thyroid carcinoma have brief flushes provoked by alcohol. In patients with watery diarrhea, hypokalemia, achlorhydria syndrome (WDHA; vasoactive intestinal peptide [VIP]omas), a purple-red constant flushing of the whole body may develop. This flushing reaction is related to the vasodilator effects of VIP. Flushes seen in mastocytosis are related to release of histamine from mast cell granules. Mastocytosis is a rare disease of mast cell proliferation that occurs both cutaneous and systemically.

So, it’s clear from our experts that the flushing symptom has many potential triggers and can be attributed to the secretion of excess hormones associated with Neuroendocrine Tumours. It’s also clear that the symptom is not just associated with carcinoid syndrome. Although many people focus on serotonin as the main culprit, some papers suggest other hormones may be playing a bigger part in this symptom, e.g. histamine (particularly foregut), tachykinins (Substance P), bradykinins, and prostaglandins.  HOWEVER, in 2023, ENETS experts stated that there is currently insufficient evidence that histamine, bradykinin, kallikrein, prostaglandins and motilin are involved in carcinoid syndrome.  Click here to find out more.

Correlation vs Causation

If you study the online forums, there are frequent questions about flushing, particularly from those looking for a diagnosis and suspecting Carcinoid Syndrome due to a flushing symptom. However…… even flushing cannot always be attributed to a NET, particularly if it’s the only symptom being presented.  And of course, many people get sweating confused with flushing – read more about sweating issues here.

This is a very useful table taken from the now out of date ISI Book which gives the tests required to determine the potential source of flushing (differential diagnosis).  I strongly suspect this is not an exact science (…..is anything in medicine?) but it’s extremely useful.  Personally, I would have included Rosacea and VIPoma.

Öberg, Grosssman, et al list the following drugs that can cause flushes:

• Bromocriptine
• Tamoxifen
• Nicotinic Acid
• Opiates
• Calcium channel blockers
• Ketoconazole
• Chlorpromazine
• Cephalosporin

Öberg, Grosssman, et al list the following foods that can cause flushes:

• Spicy food
• Glutamate
• Sodium nitrate
• Sulfites
• Hot beverages

Öberg, Grosssman, et al also list the following neurologic disorders that can cause flushes:

• Anxiety
• Migraine
• Parkinson’s disease
• Spinal cord lesions
• Brain tumours

My own experience

My own experience with flushing brings back some memories and it emphasises something I say a lot – the patient has a big part to play in their own diagnosis.  Please check out this 90 second video about how I did not play my part!  I was experiencing a mild and innocuous flushing sensation for some months before I was diagnosed with metastatic Neuroendocrine Cancer.  Even though I knew it was weird and something I hadn’t experienced before, I totally ignored it.  I failed to mention it at any of my routine GP appointments or at my annual asthma clinic.  I failed to mention it to my specialist who was investigating a GP/PCP diagnosis of Iron Deficiency Anemia/weight loss.  After a CT scan, the specialist appeared to be scratching his head …..  at that point he knew I had cancer, but he also knew it was unusual.  I suddenly mentioned the flushing and ‘bingo’.  It was the face of a man who had just found a missing piece of a jigsaw and he correctly predicted the output from my subsequent liver biopsy.  For the next few months, I was keeping my condition private at work, but it was sometimes difficult to disguise the flushing. At least one person thought my blood pressure was going up!

Following my diagnosis, I was tested for 5-HIAA which was elevated as confirmation.  Shortly after, I commenced daily injections of Octreotide. These injections reduced the flushing, but it didn’t eliminate it. However, after my ‘debulking’ surgery in Nov 2010, my flushing disappeared.  However, I do remember this small flush coming out of nowhere whilst I was recovering in hospital after that surgery. I was cleaning my teeth and I do vividly remember this minor task taking some effort!

I haven’t had a flush since and if this symptom comes back, I’ll know I have a new problem to contend with.  

You may also enjoy:

“Early diagnosis of Stage 4 Cancer”

“No sweat”

“A Spotlight on Carcinoid Syndrome”

Sources used:

1. Rastogi V, Singh D, Mazza JJ, Parajuli D, Yale SH. Flushing Disorders Associated with Gastrointestinal Symptoms: Part 1, Neuroendocrine Tumors, Mast Cell Disorders and Hyperbasophila. Clin Med Res. 2018 Jun;16(1-2):16-28. doi: 10.3121/cmr.2017.1379a. Epub 2018 Apr 12. PMID: 29650525; PMCID: PMC6108509.

2. Hannah-Shmouni F, Stratakis CA, Koch CA. Flushing in (neuro)endocrinology. Rev Endocr Metab Disord. 2016 Sep;17(3):373-380. doi: 10.1007/s11154-016-9394-8. PMID: 27873108; PMCID: PMC5161029.

3. Endocrinology: Adult and Pediatric – 7th Edition 2016 by Öberg, Grosssman et al.

4. InterScience Institute Neuroendocrine Tumors, A Comprehensive Guide to Diagnosis and Management, Fifth Edition, Eugene A. Woltering, Aaron I. Vinik, Thomas M. O’Dorisio, Vay Liang W. Go, Gregg Mamikunian, 2016

5. ENETS Guidelines on Carcinoid Syndrome

5. A Spotlight on Carcinoid Syndrome

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