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).
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.
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 tumors—the tumours’ secretions lead to clinical symptoms due to elevated levels of the assoicated hormone(s), some more distinct than others.
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 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. 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! MEN is just one of the NET related hereditary syndromes, there are others, read more here.
Major NET Syndromes
(information mainly taken from the ISI Book on NETs with a cross-reference from ENETS and UKINETS Guidelines)
The ISI Book on Neuroendocrine Tumors (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!
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. It’s a real witch’s brew!
Carcinoid syndrome occurs when biologically active amines and peptides enter the systemic circulation escaping the first pass metabolism of the liver. Normally, these bioactive products are inactivated by the liver. However, in cases of neuroendocrine tumors with liver metastasis, either these bioactive products are directly released into the systemic circulation, or they escape inactivation due to deranged liver function.
Less commonly, carcinoid syndrome can occur without liver metastasis in conditions like a primary gut tumor with extensive retroperitoneal nodal metastases, a bronchial or ovarian NET, where it’s possible for bioactive amines to be released directly into the systemic circulation.
It is reported that neuroendocrine tumors release about 40 different types of biologically active amines and peptides. The most common related to carcinoid syndrome are serotonin, histamine, tachykinins, kallikrein, and prostaglandins (read more about NET related hormones here) The majority of midgut symptoms are said to be due to serotonin which is a product of tryptophan metabolism.
Usually, only 1% of dietary tryptophan is converted into serotonin. However, in a patient with carcinoid syndrome, up to 70% of tryptophan can be converted into serotonin. Serotonin undergoes oxidative reaction and leads to the formation of 5-hydroxy indoleacetic acid (5-HIAA) by aldehyde dehydrogenase, which subsequently is eliminated into the urine.
Serotonin causes increased motility and secretion of gastrointestinal tract resulting in diarrhea. As most of the body’s tryptophan is diverted to serotonin formation pathway by neuroendocrine tumors, it can sometimes lead to a deficiency of tryptophan which is needed for synthesis of niacin. Subsequently, in extreme cases, deficiency of niacin occurs causing Pellagra which manifests as dermatitis, dementia, and diarrhea. Prostaglandins also mediate increased intestinal motility and fluid secretion in GI tract causing diarrhea.
Neuroendocrine tumors of foregut and lungs do not contain the enzyme aromatic L-amino acid decarboxylase which converts 5-hydroxytryptophan to serotonin. Thus, lungs and foregut neuroendocrine tumors do not normally produce serotonin. Hindgut neuroendocrine tumors usually do not normally produce any bioactive hormone.
Histamine is released mostly by pulmonary neuroendocrine tumors which can cause atypical flushing and pruritus. Flushing is also secondary to the vasodilatory effect of tachykinins (substance p, neurokinin A, neuropeptide k).
Pancreatic NET syndromes
Most pancreatic NETs are non-functional but there are several distinct clinial syndroems related to pancreatic NETs. 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. The main pancreatic NET syndromes are:
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.
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 somerimes known as ACTHoma.
Sweet’s – Dermatitis/rash associated with Glucagonomas. Not to be confused with Pellagra (B3 deficiency)
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 deveoping Neuroendcrine Tumours. Neuroendocrine / Endocrine tumors can be seen in several inherited familial syndromes, including but not limited to:
- Multiple Endocrine Neoplasia type 1 (MEN1)
- Multiple Endocrine Neoplasia type 2 (MEN2)
- Multiple Endocrine Neoplasia type 4 (MEN4)
- 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 Tumors
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.
SDHx mutations/Hereditary pheochromocytoma/paraganglioma syndromes
- 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, y
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.
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— Ronny Allan (@RonnyAllan1) March 3, 2016