There are some curious things about Neuroendocrine Cancer (NETs elsewhere in the text on the basis that a hormonal syndrome is extremely rare in Neuroendocrine Carcinoma (NEC)).  One of them 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.

This frequently makes NET  very difficult to diagnose quickly.  It’s a very devious disease.

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.

• Non-functioning tumours—no specific clinical syndrome is observed or excess hormone secretion isn’t sufficient enough to cause symptoms.

• Functioning tumours—the tumours’ secretions lead to clinical symptoms due to elevated levels of the associated hormone(s), some more distinct than others.

It’s useful to know about the range of tumour markers and hormone markers – read more here

Syndrome and Tumours – ‘Chicken or Egg’ ?

I’m always confused when someone says they have been diagnosed with a Syndrome rather than a NET type.  You need a tumour to produce the symptoms of a syndrome. So I guess that declaring a NET syndrome without evidence of a tumour is part guess on the basis the symptoms can have many differential diagnoses and some of the tests are not 100% specific/sensitive.

The exception to this rule 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. That means the syndrome is there first. A mutation (alteration) in the various MEN genes gives a person an increased risk of developing endocrine/neuroendocrine tumours and other symptoms of MEN. It’s also possible that the tumours will be discovered first.  It’s complex!  MEN is just one of the NET related hereditary syndromes, there are others, read more here.

Many syndromes almost always only appear when there are distant metastases.  This is particularly the case in carcinoid syndrome as the liver is unable to filter the excess  hormones due to deranged liver function.  However, there are some exceptions and this is related to mainly blood flow within the human body where the excess hormones are released directly in the systemic circulation.  Pancreatic NET syndromes are less affected by the distant metastases issue described below in carcinoid syndrome.

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.

There’s a highly prevalent issue 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 or 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 in the pancreas but it is highly unusual.  When a patient presents with vague symptoms and has a pancreatic NET, the easy option is to declare “carcinoid syndrome” rather than check for the known pancreatic NET hormones or other illnesses.  It also happens with other types of NET. Of course part of the issue is the ‘carcinoid‘ nomenclature which seems to linger like a bad smell.

Major NET Syndromes  

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.  You can see why Neuroendocrine Cancer is a diagnostic challenge!

The main ones are given below. 

Carcinoid Syndrome

Now covered in my ‘Spotlight’s series. Click here to read or on the picture below.

Pancreatic NET syndromes

Most pancreatic NETs are non-functional but may have been growing for some time presenting some symptoms including but not limited to: diarrhea, indigestion, a lump in the abdomen, pain in the abdomen or back, yellowing of the skin and whites of the eyes.

But there are several distinct clinical syndromes related to pancreatic NETs and these are normally related to highly elevated predominant hormone secretions. 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.  It’s clear from what I see in patient groups that many pancreatic NET patients believe they have carcinoid syndrome (perhaps told this by a doctor) when in fact they are experiencing symptoms of other syndromes specifically related to the pancreas area, comorbidities (other illness unrelated to NETs) or side effects of tumour growth or therapy.  Read about the incidence of carcinoid syndrome and pancreatic NETs by clicking here.

The main pancreatic NET Syndromes and their signs and symptoms are:

Insulinoma.  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 tumours that rarely spread. Some of these tumours will be associated with MEN1 syndrome.

Symptoms – too much insulin may cause:

• Low blood sugar. This can cause blurred vision, headache, and feeling lightheaded, tired, weak, shaky, nervous, irritable, sweaty, confused, or hungry.
• Fast heartbeat.

Gastrinoma.  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 and Type II Gastric NETs. Some of these tumours may be associated with MEN1 syndrome.

Symptoms – too much gastrin may cause a condition known as Zollinger-Ellison syndrome producing symptoms such as reflux, dyspepsia, ulcers, PPI-responsive diarrhea.
Vipoma.  Verner-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.

Symptoms – too much vasoactive intestinal peptide (VIP) may cause:

• Very large amounts of watery diarrhea.
• Dehydration. This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness, or feeling tired.
• Low potassium level in the blood. This can cause muscle weakness, aching, or cramps, numbness and tingling, frequent urination, fast heartbeat, and feeling confused or thirsty.
• Cramps or pain in the abdomen.
• Facial flushing.
• Weight loss for no known reason.

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 hyperglycaemia (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.    Sometimes known as the 4D syndrome – Dermatological, Diabetes, DVT, Depression.  The dermatological side effect has been described as necrolytic migratory erythema.

Symptoms – too much glucagon may cause:

• Skin rash on the face, stomach, or legs.
• High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
• Blood clots. Blood clots in the lung can cause shortness of breath, cough, or pain in the chest. Blood clots in the arm or leg can cause pain, swelling, warmth, or redness of the arm or leg.
• Diarrhoea.
• Weight loss for no known reason.
• Sore tongue or sores at the corners of the mouth.

Somatostatinoma is 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!)

Somatostatinoma – too much somatostatin may cause:

• High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
• Diarrhoea.
• Steatorrhea (very foul-smelling stool that floats).
• Gallstones.
• Yellowing of the skin and whites of the eyes.
• Weight loss for no known reason.

Several new types of Pancreatic NET hormonal syndromes were added to the ENETS guidelines in 2023.  Read more by clicking here.  I’ll list them here briefly.

ACTHoma. Representing an Ectopic Cushing’s Syndrome – see below for Cushing’s Syndrome separately.  Symptoms include Hypokalaemia, diabetes mellitus, muscle weakness, hypertension, moon facies, oedema.

PTHroma.  Humoral hypercalcemia of malignancy.  Symptoms include hypercalcemia, hypophosphataemia, elevated alkaline phosphatase.

Caltitoninoma.  High calcitonin levels, symptoms include diarrhea and flushing.

GHRoma. Ectopic acromegaly.  Elevated IGF-1 and GHRH.  Symptoms include acral overgrowth and cardiomegaly.

You may see some sites listing PPoma.  Pancreatic Polypeptide (PP).  A complicated one and not too much information (even in the now historical ISI book or ENETS Guidelines, in fact ENETS guidelines do not even list it in the recent 2022 document). 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.

Other NET or NET related syndromes

Hedinger Syndrome – the technical name for Carcinoid Heart Disease and an ideal replacement term now that Carcinoid is being phased out. Not a hormonal syndrome per se, but it can often be a manifestation of severe cases of so called carcinoid syndrome. Normally related to really high levels of 5HIAA.

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 sometimes known as ACTHoma.

Hereditary/Inherited familial syndromes

Some sites describe these as types of NET but that is totally wrong – they are recognised syndromes that increase the risk of developing Neuroendocrine Tumours.  Neuroendocrine / Endocrine tumours can be seen in several inherited familial syndromes, including but not limited to:

• Multiple Endocrine Neoplasia (click this link to read more)
• SDHx mutations – Hereditary Pheochromocytoma/Paraganglioma Syndromes.
• Von Hippel-Lindau (VHL) Disease (see below)
• Neurofibromatosis Type 1 (also known as Recklinghausen’s Disease) – associated with Duodenal/Pancreatic NETs and Pheo/Para.
• Tuberous Sclerosis – loose association restricted to case studies of many sites including pancreas, parathyroid and pituitary.
• Carney Complex – associated with adrenal and pituitary glands.

see more here Genetics and Neuroendocrine Tumours

Paraneoplastic Syndromes (or Paraneoplastic Endocrine Syndromes)

These are not the same as hormonal syndromes. They are related to the immune system and may also be ectopic in their behaviour.

There is a separate article available – click here or on the picture below:

Summary

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 diarrhea, 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’s which is a useful list of things to be wary of but context is important.

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 haemoglobin 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, vague and routine symptoms generated by a syndrome contribute to the fact that NETs are 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 NETs 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.

Related reading:

• Horrible Hormones – click here
• Tumour and Hormone Markers – click here
• A Witches Brew – click here
• Heterogeneity – click here
• ENETS Guidelines on Carcinoid Syndrome – click here
• ENETS Guidelines on Pancreatic Hormonal Syndromes – click here

Disclaimer

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.

Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional. Some content may be generated by AI which can sometimes be misinterpreted.  Please check any references attached.

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.

Click here and answer all questions to join my private Facebook group

Please Share this post for Neuroendocrine Cancer awareness and to help another patient