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 which 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, many diagnoses of NET can be extremely challenging. Even for an experienced doctor, it can be a difficult jigsaw!
Most 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 some NETs can be ‘silent’ (non-functional) for years before any symptoms show and it’s normally only when they metastasize, that these clinical syndromes come to life. Ironically, the manifestation of the disease with a syndrome can occasionally turn out to be a life saver albeit the cancer is normally incurable at this stage – but still treatable.
The most common type 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. You may find my post on the ‘5 E’s of Carcinoid Syndrome’ useful.
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. However, the flushing is reported to be different from most people’s perceptions of a ‘flush’. The Carcinoid flush is almost always ‘dry’. To quote my ‘amazing yellow book‘ (co-authored by 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 NETs guru also raises this distinction by stating…. “The facial flushing of carcinoid syndrome is usually a 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.”
Additionally, from the same source, there appears to be at least two varieties of flushing in Carcinoid Syndrome related to two different anatomical regions of the primary tumour (again a useful guide from my amazing yellow book):
What to Look For in Flushing – Distinguishing Signs and Symptoms
There are two varieties of flushing in carcinoid syndrome:
1. Midgut: The flush usually is faint pink to red in color and involves the face and upper trunk as far as the nipple line. The flush is initially provoked by alcohol and food containing tyramine (e.g., blue cheese, chocolate, aged or cured sausage, red wine). With time, the flush may occur spontaneously and without provocation. It usually lasts only a few minutes and may occur many times per day. It does not normally leave permanent discoloration.
2. Foregut tumors: The flush often is more intense, of longer duration, and purplish in hue. It is frequently followed by telangiectasia and involves not only the upper trunk but may also affect the limbs. The limbs may become acrocyanotic (painless bluish discoloration), and the appearance of the nose can resemble that of rhinophyma.
Not all flushing is carcinoid syndrome
Worth pointing out that not all hormone induced flushing is associated with so called “carcinoid syndrome”. According to Hannah-Shmouni, F., Stratakis, C.A. & Koch, C.A. Flushing in (neuro)endocrinology. Rev Endocr Metab Disord 17,373–380 (2016). https://doi.org/10.1007/s11154-016-9394-8O, other types of NET syndromes/types can have a flushing symptom, including:
Pheochromocytoma/Paraganglioma – hypertension mainly due to release of catecholamines and other hormones. Also causes sweating which may appear to be flushing/hot flash.
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, that can cause flushing and sweating.
Pancreatic NETs – only around 1% of pNETs are associated with so called “carcinoid syndrome”. While most are non-functional, they can secrete several hormones and peptides, including VIP, gastric inhibitory polypeptide, 1prostaglandin, 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 all forms of PNETs.
Cushing’s Syndrome – Endogenous Cushing syndrome is the result of chronic glucocorticoid excess from either an ACTH-secreting pituitary tumor, 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. Facial plethora is consistent and unlike flushing rarely episodic; it is also decreased after surgery, due to reduction of blood volume perfusion.
Other misc causes – see reference link above (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.
Another source for flush descriptions comes from a paid article written by well-known NET Endocrinologist – Kjell Öberg.
Four different types of flushing have been described in the literature.
Endocrinology: Adult and Pediatric – 7th Edition 2016.
The first type is the diffuse, erythematous flush, usually affecting the face, neck, and upper chest (i.e., normal flushing area). This flush is commonly of short duration, lasting from 1 to 5 minutes, and is related to early stages of malignant midgut NETs.
The second type is violaceous flush, which affects the same areas of the body and has roughly the same time course or sometimes lasts a little longer. These patients also may have facial telangiectasia. This flush is related to the later stages of malignant midgut NETs and is normally not felt by the patients because they have become accustomed to the flushing reaction.
The third type is prolonged flushing, lasting for hours up to several days. It sometimes involves the whole body and is associated with profuse lacrimation, swelling of the salivary glands, hypotension, and facial edema. These symptoms are usually associated with malignant bronchial carcinoids.
Finally, the fourth type of flushing reaction is bright red, patchy flushing, which is seen in patients with chronic atrophic gastritis and ECLomas (derived from enterochromaffin-like cells) of the gastric mucosa with evidence of increased histamine production.
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 occurrence of a tumor. Menopausal flushes usually involve the whole body and might be related to 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 signaling 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 cutaneously 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, there appears to be significant evidence to suggest that other hormones may be playing a bigger part with this symptom, e.g. histamine (particularly foregut), tachykinins (Substance P), bradykinins, and prostaglandins.
If you study the online forums, there are frequent questions about flushing, particularly from those looking for a diagnosis and are 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.
This is a very useful table taken from my amazing yellow book which gives the tests required to determine the potential source of a 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. The referenced article “>Endocrinology: Adult and Pediatric – 7th Edition 2016 by Öberg, Grosssman et al, generally agrees with this list but adds WHDA Syndrome (a pNET called VIPoma), food, drugs, ethanol and idiopathic. It also generalises Neurologic disorders (see more below).
Öberg, Grosssman, et al list the following drugs that can cause flushes:
- Nicotinic Acid
- Calcium channel blockers
Öberg, Grosssman, et al list the following foods that can cause flushes:
- Spicy food
- Sodium nitrate
- Hot beverages
Öberg, Grosssman, et al also list the following neurologic disorders that can cause flushes:
- Parkinson’s disease
- Spinal cord lesions
- Brain tumors
Clearly these lists are those that can cause a flush but not everyone will experience this. For example, when I was syndromic with flushing, I never had any issues with hot beverages.
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 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 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.
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