In my article ‘Ever wonder what caused your NET’, I concluded that currently, the only known scientifically explained causes for NETs were hereditary/genetic in nature. This is mostly associated with those who have MEN syndromes (yes, they are a syndrome not a type of tumour) and a few other less common types of NET including Pheochomocytoma/Paraganglioma (Pheo/Para) and Medullary Thyroid Carcinoma (MTC) (the familial version of MTC is often referred to as FMTC). However, please note this does not mean that all those diagnosed with pancreatic, parathyroid, pituarity, Pheo/Para and MTC tumours, will have any hereditary or genetic conditions, many will simply be sporadic tumors.
In recent years, it has become increasingly apparent that a number of Neuroendocrine tumours arise as a result of germline genetic mutations and are inherited in an autosomal dominant pattern. The number of genes implicated is increasing.
Apparently, 5-10% of Gastroenteropancreatic NETs (GEP NETs) are estimated to have a hereditary background. Syndromes associated with these include Multiple Endocrine Neoplasia (MEN), Von Hippel Lindau (VHL), Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis (TS) and others. People who have a genetic condition may present with the tumors (perhaps along with an associated syndrome) and so the genetic condition if there is one, may not be known at this point.
How will I know if I am affected?
Some people do worry about this, often because of what they find on the internet including inside patient forums. I suspect some people already know via family connections and I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise a suspicion for MEN1.
Many people say how do I know, how do I check and this is obviously a delicate subject. Of course, your first port of call should be your NET specialist if you suspect or know of any connection.
Thus why I was interested in a paper published in Springer Link – titled “When should genetic testing be performed in patients with neuroendocrine tumours.” When reading, you’ll find it’s actually much more than that! Check it out here:
When should genetic testing be performed in patients with neuroendocrine tumours?
In this review, the authors examined the features which may lead a clinician to suspect that a patient may have an inherited cause of a NET and they outlined which underlying conditions should be suspected. They also discussed what type of screening may be appropriate in a variety of situations. If there is a way to identify which patients are likely to have a germline mutation, this would enable clinicians to counsel patients adequately about their future disease risk, and allows for earlier detection of at-risk patients through family screening. There’s a couple of minor errors in the text but I’ve contacted the authors.
The authors focused on presentations of NETs of the gastrointestinal system, chromaffin cell tumours (Pheochromocytoma and Paraganglioma) and Medullary Thyroid Carcinoma. Pituitary tumors (normally associated with MEN1), were not considered in scope for the review. Interesting, the review includes news of a move by endocrinologists to reclassify ‘Pituitary Adenomas’ as Pituitary NETs (PitNETs). Read the abstract here. This would appear to be in line with a gradual shift from the benign nomenclature associated with certain NETs to the ‘malignant’ potential of these type of tumors. The abbreviation is also in line with others, e.g. pNET, SiNET, etc. A useful reminder that we must stop using the term ‘Carcinoid‘ as this is regressing this extremely useful initiative to highlight the malignant potential of all NETs.
There also appears to be some linkage to the study looking at the possibility of familial Small Intestine NETs (SiNETs). You can read more about a US registered trial here (with apologies for use of the now defunct term ‘Carcinoid‘).
This is a complex subject and the text above is very basic. If you wish to dig further, the quoted reference is a good read. Just to emphasise, it’s aim is to provide advice about when to recommend genetic testing for NETs, and in doing so provides some useful reference information. It’s broken down into 4 distinct tumor groupings:
In 2013, just when I thought everything seemed to be under control, I was told I had a ‘lesion’ on the left upper lobe of my thyroid. At the time, it was a bit of a shock as I had already been subjected to some radical surgery and wondered if this was just part of the relentless march of metastatic NET disease. The thyroid gland does in fact get mentioned frequently in NET patient discussions but many of the conversations I monitored didn’t seem to fit my scenario – cue relentless study! I’ve been meaning to write this blog for some time but here is a synopsis of my research translated into ‘patient speak’. This is intentionally brief, it’s a big subject. I’ll finish off with an update on where I am with my thyroid issue.
Where is the thyroid and what does it do?
Before I found out about my thyroid problem, I had absolutely no idea what its function was. I can tell you know, it’s a small organ but it has a massive job!
It lies in the front of your neck in a position just below your ‘Adam’s apple’. It is made up of two lobes – the right lobe and the left lobe, each about the size of a plum cut in half – and these two lobes are joined by a small bridge of thyroid tissue called the isthmus. It is sometimes described as butterfly shape. The two lobes lie on either side of your wind-pipe. The fact that it comes up a lot in NET patient discussions is hardly surprising as it’s an endocrine organ responsible for making two hormones that are secreted into the blood: Thyroxine (T4) and Triiodothyronine (T3). These hormones are necessary for all the cells in your body to work normally.
Do I have Thyroid Cancer?
I’ve had a number of biopsies on the thyroid lesion, several fine needle aspiration (FNA) and one ‘core’. The FNAs were generally inconclusive and the core confirmed fibrous tissue only. However, the general diagnosis is inconclusive and I have been labelled “THY3F”. Curiously this decodes to “an abnormality is present but it could either be a benign (non cancerous) growth or a malignant cancerous growth of the follicular cells. A quick primer on Thyroid Cancer is below if you’re interested.
The following is a list of facts regarding thyroid nodules:
Thyroid nodules are three times more common in women than in men
30% of 30-year-old women will have a thyroid nodule.
One in 40 young men has a thyroid nodule.
More than 95% of all thyroid nodules are benign (non-cancerous growths).
Some thyroid nodules are actually cysts, which are filled with fluid rather than thyroid tissue.
Purely cystic thyroid nodules (thyroid cysts) are almost always benign.
Most women will develop a thyroid nodule by the time they are 50 years old.
The incidence of thyroid nodules increases with age.
50% of 50-year-old women will have at least one thyroid nodule.
60% of 60-year-old women will have at least one thyroid nodule.
70% of 70-year-old women will have at least one thyroid nodule.
See EndocrineWeb for more detail about thyroid issues unrelated to NET.
There can be other issues with Thyroids including cancer and clearly this was my concern when the word ‘lesion’ was mentioned. At this point, it’s worth mentioning something from my cancer history which I initially assumed was related but it would appear to be a coincidence (for the time being …..). I also have a hotspot in my left supraclavicularfossa (SCF) lymph nodes (near the clavicle), geographically close to the thyroid (and my lesion is left-sided). 5 nodes were removed from this area in Feb 2012 for an exploratory biopsy which subsequently tested negative and CT and Ultrasound both show nothing vascular or pathologically enlarged. BUT …. there is still a hotspot showing on a subsequent Octreoscan since the nodes were removed in 2012. For the record, I also had positively tested nodes removed from my left axillary (armpit) during the same procedure (my distant disease has always been left-sided).
The surgeon who operated on my left axillary and SCF nodes also specialises in Thyroids and so it was an easy decision to ask to be referred to him. He explained that whilst he could just take the left lobe or the whole thyroid, it would mean lifelong treatment to add to my current burden and perhaps for something which will never trouble me. As nothing is palpable and I have no symptoms, I agreed to a ‘watch and wait’ approach. I now have regular tests and I saw him Endocrine MDT annually for a blood test review and ultrasound check (but see update below).
Latest update as at 15 Jan 2019
After monitoring for the first two years, my specialist was not happy with TSH/T4 blood results (elevated for the second time and also on a retest). On 20 March 2018, following an Endocrine appointment, I was put on a trial dose of 50mcg of Levothyroxine to counter the thyroid panel results indicating mild hypothyroidism. Levothyroxine is a thyroid hormone replacement. My subsequent two x thyroid panel results are back in the middle of the range so all is good. Am detecting a slight increase in available energy.
The results of my first Ga68 PET scan in June 2018 indicated some “uptake” but the report inferred it was physiological uptake (false positive). In fact, at my 2019 appointment, the thyroid lesion is slightly smaller on the latest ultrasound. I’m personally fairly certain this is not connected to NETs and my Endocrine MDT have now referred me back to be survellanced by the NET MDT, they remain on call for any issues.
What else can go wrong with a thyroid?
Apart from cancer, the main issues appear to be an underactive Thyroid or an overactive Thyroid – known respectively as Hypothyroidism (not enough thyroxine is produced for the body’s needs) and Hyperthyroidism (too much thyroxine is produced for the body’s needs). Of course, these issues can be caused or made worse by cancer.
Hypothyroidism – If too little of the thyroid hormones are produced, the cells and organs of your body slow down. If you become hypothyroid, your heart rate, for example, may be slower than normal and your intestines work sluggishly, so you become constipated. Key symptoms: tiredness, feeling cold, weight gain, poor concentration, depression. Some of these symptoms look familiar? The word ‘hashimoto’s’ also comes up on patient forums frequently – this is related to hypothyroidism (underactive).
Hyperthyroidism – If too much of the thyroid hormones are secreted, the body cells work faster than normal, and you have Hyperthyroidism. If you become hyperthyroid because of too much secretion of the hormones from the thyroid gland, the increased activity of your body cells or body organs may lead, for example, to a quickening of your heart rate or increased activity of your intestine so that you have frequent bowel motions or even diarrhoea. Key symptoms – weight loss, heat intolerance, anxiety, and, sometimes, sore and gritty eyes. Hmm, again, some of these look familiar?
Check out this excellent short video from WebMD – click here or the picture below. It’s based on USA but most of it is relevant globally.
It’s also worth noting that somatostatin analogues might cause a “slight decrease in Thyroid function” (it actually states words to this effect in the Lanreotide and Octreotide patient leaflets). Thus why I advise you not to be underactive with your Thyroid surveillance – read more click here
Routine ‘Thyroid blood tests’ from your doctor will confirm whether or not you have a thyroid disorder. I now test for TSH (thyroid-stimulating hormone), T3 and T4 every 6 months. My levels are back to normal ranges since being prescribed thyroid hormone replacement therapy.
Remember: Hypo is ‘underactive’, Hyper is ‘overactive’. Sometimes there are very few symptoms.
Also worth mentioning something called the ‘Parathyroid’ as these glands can frequently be related to NET Cancer (see my blog on Multiple Endocrine Neoplasia(MEN)). It’s another subject in its own right but I just wanted to emphasise that this is a totally different organ with a totally different function (it regulates Calcium). They are located adjacent to the Thyroid, thus the term ‘para’.
Quick primer on Thyroid Cancer
There are a number of different types of Thyroid Cancer
Papillary thyroid cancer is the most common type of thyroid cancer, accounting for about 80% of thyroid cancers. While papillary thyroid cancer typically occurs in only one lobe of the thyroid gland, it may arise in both lobes in up to 10% to 20% of cases. Papillary thyroid cancer is most common in women of childbearing age. It sometimes is caused by exposure to radiation. Even though papillary thyroid cancer is usually not an aggressive type of cancer, it often metastasizes (spreads) to the lymph nodes in the neck. Papillary thyroid cancer treatment usually is successful.
Follicular thyroid cancer accounts for about 10% of thyroid cancers. Like papillary thyroid cancer, follicular thyroid cancer usually grows slowly. Its outlook is similar to papillary cancer, and its treatment is the same. Follicular thyroid cancer usually stays in the thyroid gland but sometimes spreads to other parts of the body, such as the lungs or bone. However, it usually does not spread to lymph nodes. It is more common in countries where diets do not contain enough iodine.
There is a type of thyroid tumour which has recently been removed as a type of cancer. “Encapsulated follicular variant of papillary thyroid carcinoma” is now known as “noninvasive follicular thyroid neoplasm with papillary thyroid-like nuclear features” or NIFTP. The word ‘carcinoma’ has gone. Read about this here.
Hurthle cell carcinoma, also called oxyphil cell carcinoma, is a type of follicular thyroid cancer. Most patients diagnosed with Hurthle cell cancer do well, but the outlook may change based on the extent of disease at the time of diagnosis.
Medullary thyroid cancer (MTC) is the only type of thyroid cancer that develops in the parafollicular cells of the thyroid gland. It accounts for 3% to 10% of thyroid cancers. Medullary cancer cells usually make and release into the blood proteins called calcitonin and/or carcinoembryonic antigen, which can be measured and used to follow the response to treatment for the disease. Sometimes medullary cancer spreads to the lymph nodes, lungs or liver before a nodule is found or the patient has symptoms. MTC can be treated more successfully if it is diagnosed before it has spread. There are two types of MTC:
Sporadic MTC is more common, accounting for 85% of medullary thyroid cancers. It is found mostly in older adults and is not inherited.
Familial MTC is inherited, and it often develops in childhood or early adulthood. If familial MTC occurs with tumours of certain other endocrine organs (parathyroid and adrenal glands), it is called multiple endocrine neoplasia type 2 (see my blog on MEN 2).
Anaplastic thyroid cancer is the most dangerous form of thyroid cancer. It is makes up only 1% of thyroid cancers. It is believed that anaplastic thyroid cancer grows from a papillary or follicular tumour that mutates further to this aggressive form. Anaplastic thyroid cancer spreads rapidly into areas such as the trachea, often causing breathing difficulties. Anaplastic thyroid cancer sometimes is called undifferentiated thyroid cancer because the cells are so different from normal thyroid tissue.
Thyroid cancer is not very common but diagnoses are ‘skyrocketing’ most likely due to advanced detection techniques. Most are very slow-growing with 5 year survival of 97% according to MD Anderson. There is a very interesting article about the overdiagnosis of Thyroid cancer which I found useful given my situation. You can read it here.
Thyroid ‘nodules’ would appear to be very common with 50-70% of all 50-70 year olds having at least one nodule present and statistically, 95% of these are benign (see EndocrineWeb).
We all know that Neuroendocrine Tumours (NETs) and their syndromes are complex but there is even more complexity to be found in a group of related disorders known as Multiple Endocrine Neoplasia (MEN). I recommend all NET patients should try to understand the basics of MEN and vice versa, particularly as both conditions seem to come with a plethora of endocrine related effects.
MEN patients will normally have a tumour in at least two endocrine glands – thus the terms ‘Multiple’ and ‘Endocrine’ (tumours can also develop in other organs and tissues). Neoplasia is just another name for tumour and these can be non-cancerous (benign) or cancerous (malignant) with the potential to metastasize.
MEN syndromes can comprise varying combinations of tumours and many will be aware of the tumour risks from family knowledge. So putting the heredity aspects to one side, it’s potentially an extremely challenging surveillance and subsequent diagnostic scenario if (and when) these risks are realised. To add to the complexity, some of the associated tumours can be sporadic (non hereditary) classic Neuroendocrine Tumours in various locations.
MEN is actually an umbrella term for a number of types (syndromes) of the disease – MEN1, MEN2a and 2b (2b was formerly MEN3). There’s a new kid on the block called MEN4 which is extremely rare.
In the most basic of terms regarding the relationship with tumours:
MEN1 seems to be centred on tumours of the parathyroid glands, the pituitary gland, and the pancreas (the 3 P’s).
MEN2a mainly focuses on medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia or adenomas (causing hyperparathyroidism), and occasionally cutaneous lichen amyloidosis.
MEN2b medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, and often a marfanoid habitus and other skeletal abnormalities.
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. Also referred to as MENX Possible association with tumors of the adrenals, kidneys, and reproductive organs.
What is particularly distinctive with MEN is that they are inherited disorders (familial). That means that they can be passed down in families, with each child of an affected parent having a 1 in 2 or 50% risk of inheritance. Consequently genetic screening/testing is normally undertaken in established MEN families and those at risk of MEN.
You may also have heard of other rare NETs with a familial aspect, in particular Pheochromocytomas (adrenal gland tumours) and Paragangliomas (outside the adrenal gland), Not all are inherited and I mention them because of the connection with MEN2a and 2b.
I’m grateful to my friend and MEN patient Linda Hageman for supporting my blog activities and also for allowing me to join the AMEN support group to learn more. This is one of the friendliest and well run support groups I’ve seen. On this site, you will find Dr Mark Lewis, an Oncologist and MEN patient who supports Linda (who is a Nurse) with a ‘Ask the Doctor’ section on their website.
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.