Around 2001, I started noticing some issues on my nose, particularly around the creases, an issue I still experience today. It normally starts with a stinging feeling, an indication I’m about to experience some sort of inflammation. What eventually happens is something which looks like a ‘whitehead’ which I now know to be a ‘pustule’. Sometimes there are multiples and most are not normally bigger than 2mm, mostly smaller. These pustules nearly always disappear within a short period of time, normally after washing/showering but they tend to leave reddish marks which eventually fade. Very infrequently, these pustules would appear on my chin. After 18 years of the issue, my nose is slightly discoloured and more reddish than the rest of my face.
Shortly after I started experiencing this issue, a doctor diagnosed me with ‘mild rosacea‘. If this is a correct diagnosis, then I would appear to have Subtype 2 or papulopustular (acne) rosacea (see breakdown of types below). I also have the minor irritation of a recurrent mild eczema inside my right outer ear which has run parallel to this issue (…. spookily).
For around two years, I was treated with a mixture of low dose oral antibiotics (tetracycline) and a skin medication known as metronidazole. This did clear up the issue but it always returned and I stopped the medication opting instead for a commercial product which I find works better. It doesn’t clear it 100% but I’ve learned to live with it and it is a long-term chronic condition. I looked at many Rosacea sites online and none of the pictures seemed to apply to me and I agree with my diagnosing doctor in terms of a ‘mild’ version.
I worked out early on that the triggers were stress, when ‘run down’, and too long in the sun. There were possibly others. Stress was part and parcel of the work I was involved in and it was at a time when I left my life in the military after 29 years and started a second career in industry (often I think in hindsight, I may have been overly stressed at the life change without realising it). Without any medical input, I decided to try to make sure I got sufficient vitamins and I now appear to get less coughs and colds then I used to. I now try to stay out of the direct sun. Other common triggers are listed on reputable sites andinclude alcohol, hot and cold weather, exercise, hot baths and spicy foods.
What is Rosacea
A common skin condition, usually occurring on the face, which predominantly affects fair-skinned but may affect all skin types in people aged 40 to 60 years old. It is more common in women but when affecting men, it may be more severe. It is a chronic condition, and can persist for a long time and, in any individual, the severity tends to fluctuate. Rosacea tends to affect the cheeks, forehead, chin and nose, and is characterised by persistent redness caused by dilated blood vessels, small bumps and pus-filled spots similar to acne. There may also be uncomfortable inflammation of the surface of the eyes and eyelids. I found this site to be a very useful Rosacea reference.
Rosacea is sometimes classified into 4 subtypes that may overlap:
Subtype one, known as erythematotelangiectatic rosacea (ETR), is associated with facial redness, flushing, and visible blood vessels.
Subtype two, papulopustular (or acne) rosacea, is associated with acne-like breakouts, and often affects middle-aged women.
Subtype three, known as rhinophyma, is a rare form associated with thickening of the skin on your nose. It usually affects men and is often accompanied by another subtype of rosacea.
Subtype four is known as ocular rosacea, and its symptoms are centred on the eye area.
What causes rosacea?
The cause of rosacea is not fully understood. Your genetics, immune system factors, and environmental factors may all play a part. Factors that trigger rosacea cause the blood vessels in the skin of the face to enlarge (dilate). The theory that rosacea is due to bacteria on the skin or in the gut has not been proven. However, antibiotics have proven helpful to treat rosacea. This is because of their anti-inflammatory effect. Rosacea is not contagious.
Why is rosacea sometimes linked to NETs?
On certain sites and in certain texts about NETs, you will see mention of Rosacea, clearly as a misdiagnosis of someone who presents with flushing. I started experiencing the sensation of NET related flushing in late 2009/early 2010 and I can honestly say this was a totally different experience to what I had with my mild rosacea. However, I don’t have the ‘blushing’ type of rosacea and I can see the presentational similarities.
Another issue commonly reported in both conditions is small visible blood vessels on the face, known formally as Telangiectasia or informally as ‘spider veins’ or ‘broken capillary veins’. This is quite common with erythematotelangiectatic rosacea (subtype 1). I actually have at least two of these showing and this appears to be something I’ve only noticed since NET diagnosis and only in the last few years. Interesting it says this is something normally caused by “chronic flushing” but I wouldn’t have labelled by flushing in that way. I have not felt any flushing since late 2010 after surgery and commencement of long acting somatostatin analogues. Unless there has been something ‘sub-clinical’ going on, I’ve veered my minor issue towards long-term but mild rosacea as the cause rather than NETs. Telangiectasia is mentioned in many NET texts including my own article “Neuroendocrine Cancer: A Witch’s Brew of Signs and Symptoms”
Histamine if often linked to both conditions. Read about NET related histamine here and Rosacea histamine issues here.
I’ll be honest with you, I’m actually not 100% convinced I have rosacea as it has similarities with many other skin conditions. In fact, skin issues are pretty common with NET patients, some are actually directly linked to NETs including Merkel Cell Carcinoma, pellagra (linked to Carcinoid Syndrome) and Sweet’s syndrome (linked to Glucagonoma). In addition, many people develop skin issues as a side effect of treatment. Read more here.
One of the curious things about Neuroendocrine Cancer (NETs going forward) is that it can very often exhibit one or more vague symptoms collectively known as a ‘syndrome’. Syndrome is an apt word to describe these complications as the most general meaning in medical terms is a group of symptoms that together are characteristic of a specific disorder or disease”. Having a syndrome can often be the difference between having a ‘functional’ condition or a non-functional’ condition – see more below.
This frequently makes Neuroendocrine Cancer very difficult to diagnose quickly. It’s a very devious disease.
It’s not all about Carcinoid Syndrome!
Most people think of Carcinoid Syndrome when they discuss NETs. Anyone suggesting that all NET patients get carcinoid syndrome or that all symptoms of NETs are caused by carcinoid syndrome, is WAY off the mark. Firstly, not everyone will have a ‘syndrome’ in addition to their tumours – the percentage is actually well below 50%. Secondly, there are in actual fact, several associated syndromes depending on the anatomical location and type of NET. As an example of one syndrome, statistics vary from source to source but it is estimated that around a 30-45% of all ‘midgut’ patients will present with metastatic disease and around a third of those (∼10-15% of all midgut) will exhibit Carcinoid Syndrome indicating their tumours are ‘functional’ (secreting excess hormones, particularly serotonin). It follows that Carcinoid Syndrome itself is not that common and it could be the same with other types of NET (even though it can appear more prevalent on forums).
Functional / Non-Functional
These tumours and associated syndromes are treatable for most but the difficult part can be arriving at a diagnosis. Moreover, without a syndrome, some of these tumours can be silently growing and as they grow slowly, the ‘silence’ can go on for some years. Even with a syndrome, the root cause can remain disguised as the symptoms are similar to many day-to-day illnesses, again the reason for the title of this blog. Curiously, the lack of a syndrome can sometimes lead to an even later presentation and the consequences that arise (i.e. no signs to aid a diagnosis). In fact a large proportion of Pancreatic NETs are non-functional at diagnosis. There can be the odd exception but in general terms, NETs are either functional (with a syndrome) or non-functional (no syndrome). It’s also possible that patients can move from one state to another.
It’s useful to know about the range of tumor markers and hormone markers – read more here
Syndrome and Tumors – ‘Chicken or Egg’ ?
I’m always confused when someone says they have been diagnosed with a Syndrome rather than a NET type. You normally need a tumor to produce the symptoms of a syndrome.
The exception might be hereditary syndromes e.g. MEN. MEN syndromes are genetic conditions. This means that the cancer risk and other features of MEN can be passed from generation to generation in a family. A mutation (alteration) in the various MEN genes gives a person an increased risk of developing endocrine/neuroendocrine tumors and other symptoms of MEN. It’s also possible that the tumors will be discovered first. It’s complex!
Major NET Syndromes
(information mainly taken from the ISI Book on NETs with a cross-reference from ENETS and UKINETS Guidelines)
TheISI Book on Neuroendocrine Tumors 2016(Woltering et al) confirms there are a number of syndromes associated directly and indirectly with NETs and are described as individual syndromes according to their secretory hormones and peptides. The reference publication expands on this list to aid diagnoses by including common presentations, associated tumour types and locations and the offending secreting hormones. You can see why Neuroendocrine Cancer is a diagnostic challenge!
Carcinoid – a syndrome connected with (mainly) serotonin secreting tumours in certain locations (mainly small intestine, lung, stomach, appendix, rectum). The key symptoms include diarrhoea, flushing of the skin (particularly the face), stomach cramping, heart problems such as palpitations, and wheezing. The syndrome is actually caused by the release of a number of hormones, in particular Serotonin, Bradykinin, Tachykinin (Substance P), Histamine, and Prostaglandins.
(there’s also a very rare instance of pancreatic based tumours producing carcinoid syndrome effects – according to ENETs less than 1% of all tumours associated with carcinoid syndrome)
Whipple’s Triad – Whipple’s Triad is the classic description of insulinoma which includes symptoms of hypoglycemia with a low blood glucose concentration relieved by the ingestion of glucose. These tumours can be located anywhere within the pancreas in the cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. Some of these tumours will be associated with MEN1 syndrome.
Zollinger-Ellinson Syndrome. A tumour that forms in cells that make gastrin and can be known as a Gastrinoma. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. This is a condition in which one or more tumours form in the pancreas, the upper part of the duodenum or the stomach (these organs are very close and tightly packed together). These tumours secrete large amounts of the hormone gastrin, which causes your stomach to produce too much acid. The excess acid can lead to peptic ulcers, in addition to diarrhea and other symptoms. Associated with Gastrinoma (pNET) and Gastric NETs. Some of these tumours may be associated with MEN1 syndrome.
Werner-Morrison Syndrome. Vasoactive Intestinal Peptide (VIP) is secreted thus the pNET term – VIPoma – Sometimes the syndrome is referred as WDHA – Watery Diarrhea, Hypokalemia (potassium deficiency), and Achlorhydria (absence of hydrochloric acid in gastric secretions). Sometimes known as Pancreatic Cholera. Some of these tumours may be associated with MEN1 syndrome
Glucagonoma. A tumour that forms in cells that make make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar) rendering most patients diabetic. A glucagonoma usually forms in the tail of the pancreas. Some of these tumours may be associated with MEN1 syndrome. See also Sweet’s Syndrome below. Sometimes known as the 4D syndrome – Dermatological, Diabetes, DVT, Depression.
Somatostatinomais a very rare type of NET, with an incidence of one in 40 million persons. These tumours produce excess somatostatin arise from the delta cells in the pancreas, although these cells can also be present in duodenal/jejunum tissue where around 44% of these tumours occur. Somatostatin is a naturally occurring peptide that inhibits the function of almost all gut hormones (author’s note – this fact should give you an appreciation of how somatostatin analogues tackle associated syndromes whilst giving you certain side effects as a result!)
Pancreatic Polypeptide (PP) – PPoma. A complicated one and not too much information (even in the ISI book or ENETS Guidelines). However, it’s the third most common type of islet cell tumour (i.e. pNET). The function of pancreatic polypeptide is not completely understood. Patients present with weight loss, jaundice, and abdominal pain. The diagnosis is confirmed by pancreatic polypeptide levels > 300 pg/ml. Some of these tumours may be associated with MEN1 syndrome.
Cushing’s – also known as hypercortisolism. A collection of symptoms caused by very high levels of a hormone called cortisol in the body. In Cushing’s disease, oversecretion of pituitary ACTH induces bilateral adrenal hyperplasia. This results in excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone. Cushing’s disease, a subset of Cushing’s syndrome, is due to a pituitary corticotroph adenoma and results in a partial resistance to the suppression of ACTH by cortisol so that secretion is unrestrained. In contrast, causes of Cushing’s syndrome may include the following:
• Adrenal adenoma or carcinoma arise spontaneously. ACTH levels are undetectable.
• Non-pituitary (ectopic) tumours produce ACTH. They most frequently originate in the thorax and are highly aggressive small cell carcinomas of the lung or slow- growing bronchial or thymic carcinoid tumours. Some produce corticotropin- releasing hormone (CRH) instead, which stimulates pituitary ACTH secretion and can therefore mimic a pituitary tumour.
• Other causes include NETs of the gastric, pancreatic, and intestinal organs; Pheochromocytomas, and MCT.
The hallmark of Cushing’s syndrome is that ACTH levels are partially resistant to suppression with dexamethasone, even at very high doses. Some MEN patients with pituitary tumours may have Cushing’s Syndrome. AdrenoCorticoTropic Hormone (ACTH) releasing tumours are somerimes known as ACTHoma.
Sweet’s – Dermatitis/rash associated with Glucagonomas. Not to be confused with Pellagra (B3 deficiency)
Neuroendocrine / Endocrine tumors can be seen in several inherited familial syndromes, including but not limited to:
MEN1 – Mainly involved the 3 Ps, Pituitary, Pancreas and Parathyroid. The pituitary tumours are primarily Prolactinomas, the pancreatic tumours are mainly PPomas, Gastrinomas and Insulinoma. Many also have association with Zollinger-Ellinson syndrome (ZES). Sometimes known as Wermer Syndrome. Associated with the MEN1 gene.
MEN2A– associated with the RET gene, can result in Medullary Thyroid Carcinoma, Pheochromocytoma, and overactive parathyroid glands characterised by a high calcium level.
MEN2B. An inherited disorder characterised by the certain development of Medullary Thyroid Carcinoma, plus the possible development of pheochromocytomas and characteristic tumours (mucosal neuromas) of the lips, tongue and bowels. Parathyroid disease is extremely rare in MEN2B. Also connected with the RET gene.
MEN4. A relatively new MEN variant and related to the CDKN1B gene. Similar to MEN1 but normally only 2 of the 3 Ps, parathyroid and pituitary; and potentially other places.
Succinate dehydrogenase (SDH) is an enzyme which is important for the metabolic function of mitochondria. Patients with mutations of these genes have increased risk of pheochromocytomas, paragangliomas, stomach tumors and kidney tumors.
SDHx mutations (SDHA, SDHB, SDHC, and SDHD) can present as Pheochromocytomas/Paragangliomas and other non-NET conditions. If this interests you see site http://www.SDHcancer.org
Von Hippel-Lindau (VHL) – not an exclusively NET syndrome. VHL is a rare disorder caused by a faulty gene. It is named after the two doctors who first described the disease, and affects about one in 35,000 people. Tumours develop in one or more parts of the body. Many of these tumours involve the abnormal growth of blood vessels in parts of the body which are particularly rich in blood vessels. Areas most frequently affected are the eyes, the back of the brain (cerebellum), the spinal cord, the kidneys, the adrenal glands and the pancreas. People are affected differently, even within the same family. The only VHL tumour which tends to run in families affects the adrenal glands (Pheochromocytoma). Different VHL features tend to develop at different ages. The eye angiomas often develop in childhood. Others, including tumours found in the cerebellum, spinal cord or adrenal glands (Haemangioblastomas and Pheochromocytomas) can develop from late childhood onwards. The kidney tumours are usually the last things that develop, from the mid-twenties onwards. Most VHL related tumours are benign.
As for my own experience of syndromes, I did once show symptoms of the most common NET syndrome (currently known as Carcinoid syndrome) where the key symptoms include diarrhoea, flushing of the skin (particularly the face), stomach cramping, heart problems such as palpitations, and wheezing. You can see why those symptoms are frequently and easily confused with other conditions. If you have a similar diagnosis, you may benefit from looking at something known as The 5 E’swhich is a useful list of things to be wary of.
I did have issues for a year or two in 2010 leading up to diagnosis and until my treatment was underway. I was experiencing flushing and infrequent bouts of diarrhea but I totally ignored it (hear me talk about this). However, it ended up being instrumental in my diagnosis albeit some good luck was involved in getting to that point. My twist of fate which involved a low hemoglobin score led me to a scan and ‘bingo’. I had a ‘gastrointestinal blip’ some 18 months previously but that proved colonoscopy negative. Despite my distant and metastatic tumour disposition and seemingly late diagnosis, I’m current non-syndromic due to “early” intervention and good treatment. However, my ongoing treatment continues to play its part.
For many,the vague and routine symptoms generated by a syndrome contribute to the fact that NET Cancer is frequently misdiagnosed with some people suffering from the side effects for many years before a correct diagnosis is made.
There are many other less known syndromes that appear to be directly or indirectly connected with Neuroendocrine Tumours and I may update this post if I discover they are more prevalent than I think. Please let me know if you’ve been told you have a NET related syndrome not listed.