Neuroendocrine Cancer is one of a number of “difficult to diagnose” conditions. Many types of Neuroendocrine Cancer come with an associated syndrome and these syndromes can mimic everyday illnesses. In some cases, many people don’t feel ill while the tumours grow. Most types of this cancer are slow-growing but there are also aggressive versions. Although things appear to be improving in diagnostic terms, it can sometimes take years for someone to be finally diagnosed correctly and get treatment, albeit in some cases, too late for any hope of a curative scenario. It’s a very sneaky type of cancer and if left too long it can be life threatening – CLICK HERE to find out why.
The road to a diagnosis of Neuroendocrine Cancer is often not straight or easy to navigate. It’s not only a sneaky type of cancer but it’s also very complex. It’s a heterogeneous group of malignancies with a varied and confusing histology and nomenclature to match. As I said above, many people are asymptomatic for years whilst the tumor grows and some might say that it’s somewhat ‘lucky’ to have symptoms to help aid a diagnosis. Many find that a lack of knowledge of Neuroendocrine Cancer in primary care, doesn’t always produce results. Common misdiagnoses include (but not limited to), Irritable Bowel Syndrome (IBS) and other common digestive diseases, menopause, appendicitis, hypertension, gastritis, asthma. Neuroendocrine Cancer is much more likely to be diagnosed at secondary care if a referral for ‘something’ can be achieved.
……..cue internet searches (Dr Google)
I think the rise and the power of the internet and rise of social media applications is very much helping generate awareness and knowledge of Neuroendocrine Cancer and those looking for a diagnosis may find help in this way. I suspect this instant access to information has played its part in the diagnostic improvements I mentioned above. Take my own efforts for example, I’m a wee Scottish guy with a computer and I’m already accelerating towards a million blog views – there’s clearly a market for what I produce. In terms of those looking for a diagnosis, if only one gets an earlier diagnosis due to my site, I’ll be happy.
Unfortunately, the internet can often be a minefield and in many cases, can lead to quite unnecessary worry for those looking for a solution.
I’m contacted almost daily by the ‘undiagnosed’ who suspect they have Neuroendocrine Cancer, often because they appear to be displaying the symptoms of one of the associated syndromes. These are some of my most difficult questions. I’m always very wary of initially agreeing with their assumptions and logic, instead opting for straightforward detective work based on my knowledge of the different types of Neuroendocrine Cancer, knowledge of the best scans, tumour markers, hormone markers. And I always warn them that statistically, they are more likely to have a common condition than the less common Neuroendocrine Cancer.
Many have already had multiple doctor’s appointments and tests. If they have not yet had a scan, I encourage them to try to get one ‘by hook or by crook’. Despite what you read on patient forums and surveys, the vast majority of Neuroendocrine diagnoses will be triggered by a conventional imaging such as CT and/or MRI. If you can see it, you can detect it.
When I first chat with the ‘undiagnosed’, I find many of them are fairly knowledgeable about Neuroendocrine Cancer and other health conditions, again confirming the power of the internet and the savvy ‘internet patient’. This is fine if you look in the right places of course – for certain things there are more wrong places on the internet than right ones.
If I have time, I’m happy to chat with these people, some are very frustrated – in fact some are so frustrated that they just want a diagnosis of something even if that something is really bad. Some are not showing anything on any scan but in certain cases, it can be likened to finding a needle in a haystack.
What do you say to someone who is utterly convinced they have Neuroendocrine Cancer but CT/MRI/Octreoscan/Ga68 PET are all clear, Chromogranin A and 5HIAA are in range but they still say they have (say) diarrhea with its potential for literally thousands of differential diagnoses. It’s a tough gig.
My scan came back normal. That should be good news. But, if there is no tumor, how can I be suffering from all the symptoms of carcinoid syndrome? Is that diagnosis wrong? Are the urine and blood test results wrong? I’m awaiting a MRI scan to take another look to see if the doctor can find anything. I don’t know what they’ll find. I don’t want them to find anything. But I’m afraid of what will happen if they don’t.
I always let the undiagnosed know that Neuroendocrine Cancer patients are some of the most friendliest and helpful people you can meet, they will treat you as one of their own. There will be a number of diagnosed people online who have gone through what the undiagnosed are going through, so they will both sympathise and emphasise. But … this can often have the adverse effect of pushing them into believing they must have Neuroendocrine Cancer. This makes for interesting discussions given the number of people who automatically assume that ‘flushing’ or ‘diarrhea’ (as described by the undiagnosed) must be Neuroendocrine Cancer without any reference to the many differential diagnoses and the context of what that actually means in Neuroendocrine Cancer terms.
10 Questions to ask your doctor/specialist for those Diagnosed with Neuroendocrine Cancer (and where to find a specialist)
I once wrote an article for DIAGNOSED NET Patients suggesting 10 Questions to ask their doctor. So I wanted to take a step back in context, using the knowledge I now have, and put myself in the shoes of someone who thinks they may have Neuroendocrine Cancer but is not yet diagnosed.
Key questions to ask your doctor/specialist for those trying to confirm or discount Neuroendocrine Cancer
Dear undiagnosed people. I totally understand your fear. There’s nothing worse than being ill and not knowing what illness you have. I’ve therefore compiled a list of 3 key questions for you to ask – think of it as a tick list of things to ask your doctor to do or check . I have linked several background articles for you to prepare your case. However, I cannot promise your doctor will agree or take any action, in fact some might be annoyed about the lack of trust. However, doing your homework really helps, including diaries and other evidence.
I also wouldn’t say that a negative to all the questions will mean you definitely do not have Neuroendocrine Cancer but at least these questions might provide your doctor and yourself with some food for thought, perhaps leading to the diagnosis of ‘something’. The questions below assume that routine blood tests have been done, including Full Blood Count, Liver, Renal, Bone, Glucose.
Questions for the UNDIAGNOSED to ask their treating physician
“I think I might have a type of cancer known as Neuroendocrine Cancer or Neuroendocrine Tumours (NET) because <<< insert your own story>>>. Would you please consider the following tests and checks:”
1. Chromogranin A (CgA) is a marker which is quite sensitive for Neuroendocrine Tumours, essentially measuring tumour bulk potentially indicating the presence of Neuroendocrine Tumours. There can be other reasons for an elevated CgA figure, including the patient’s use of proton pump inhibitors (PPI) (see the article for an alterative test where this is the case). Read more here – Neuroendocrine Cancer – Tumour and Hormone Marker tests.
3. Scans. Most NETs can be seen on a CT scan although liver metastasis can often show more clearly on an MRI. There are also nuclear scan options to confirm conventional imaging findings. Some NETs may be accessible via endoscopy and ultrasounds can also give hints for further investigation. In some cases, nuclear scans will find things that conventional imaging cannot because radionuclides can normally pick up oversecreting tumours. Read more in my article “If you can see it, you can detect it”.
You can hear two NET specialists talking about the issues surrounding the diagnostics here.
ASCO (American Society of Clinical Oncology) is one of the biggest cancer conferences in the world normally bringing together more than 30,000 oncology professionals from around the world to discuss state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field. As Neuroendorine Tumors is on a roll in terms of new treatments and continued research, we appear to be well represented with over 20 ‘extracts’ submitted for review and display. This is fairly complex stuff but much of it will be familiar to many. I’ve filtered and extracted all the Neuroendocrine stuff into one list providing you with an easy to peruse table of contents, complete with relevant linkages if you need to read more. For many the extract title and conclusion will be sufficiently educational or at least prompt you to click the link to investigate further. Remember, these are extracts so do not contain all the details of the research or study. However, some are linked to bigger trials and linkages are shown where relevant. I’ve also linked to some of my blog posts to add context and detail.
I’m hoping to capture any presentations or other output from the meeting which appears to be relevant and this will follow after the meeting. I will also be actively tweeting any output from the live event (for many cancers, not just NETs).
There’s something for everyone here – I hope it’s useful.
Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.
Check out my recent blog discussing ‘Theranostic pairing” – click here
Conclusions: The duration of SSA use was positively associated with QoL benefit among CS patients. This may be explained by long-term effectiveness of SSAs or selection bias favoring patients with more indolent disease. Future studies will be needed to distinguish between these possibilities.
Conclusions: The incidence of weight gain was dose-related on TE and was greater than that on pbo. It was possibly related to a reduction in diarrhea severity, and it may be a relevant aspect of TE efficacy among patients with functioning metastatic NETs. Clinical trial information: NCT01677910
Conclusions: A pre-PRRT analysis of circulating NET genes, the predictive quotient index comprising “omic” analysis and grading, is validated to predict the efficacy of PRRT therapy in GEP and lung NETs.
Conclusions: CAPTEM shows activity in neuroendocrine tumor of unknown primary. Currently FDA approved treatment options for grade I and grade II GI NETs includes somatostatin analogs and everolimus. Both of which are cytostatic and of limited use in case of visceral crisis or bulky disease where disease shrinkage is required. CAPTEM should be considered for grade II NETS of unknown primary.
Conclusions: This is the first multi-center study in Mexico. Which reflects the clinical characteristics of the NET_GET. The results differ in their epidemiology from that reported in other countries. However, the clinical and therapeutic results are very similar.
Conclusions: These data suggest that serotonin is secreted by nonfunctioning tumors, but does not reach the threshold required for clinical carcinoid symptoms. Monitoring 5HIAA and CgA may be useful during LAN treatment of nonfunctional GEP NETs. Clinical trial information: NCT00353496
Conclusions: CLARINET OLE suggests sustained antitumor effects with LAN 120 mg in enteropancreatic NETs irrespective of tumor origin, and suggests benefits with LAN as early treatment. Clinical trial information: NCT00842348
Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN regardless of prior OCT use. Transition from OCT to LAN was well tolerated among prior OCT pts in ELECT. Clinical trial information: NCT00774930
Conclusions: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.
Conclusions: In this poor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.
Conclusions: Occurrence of documented carcinoid crisis was low in this high-risk population. However, a significant proportion of patients developed hemodynamic instability, suggesting that carcinoid crisis is a spectrum diagnosis and may be clinically under-recognized. Use of octreotide was not associated with risk of carcinoid crisis or hemodynamic instability; however, this analysis was limited by our modest sample size at a single institution. There remains a need to establish an objective definition of carcinoid crisis and to inform standardization of periprocedural use of octreotide for at-risk patients.
Conclusions: By assessing patients with GI NET from two independent US claim databases, this study suggested that patients diagnosed with CS were 2-3 times more likely to be diagnosed with liver disorder, enlargement of lymph nodes, or abdominal mass, than those without CS during the one year prior to CS diagnosis. Future studies using patient medical charts are warranted to validate and interpret the findings. These findings, when validated, may aid physicians to diagnose CS patients earlier.
Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be considered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.
Conclusions: To the best of our knowledge, this is the first population-based study to examine potentially relevant pre-existing symptoms, resource utilization and healthcare costs before NET diagnosis. NET patients were more likely to have certain conditions and incurred higher resource utilizations and costs in the year preceding diagnosis of NET.
Conclusions: This population-based study showed that elderly NET pts have significantly different prevalence of co-morbidities compared to non-cancer controls. The impact of these conditions on survival and therapeutic decisions is being evaluated.
Conclusions: In patients with SBNET with liver metastasis, higher tumor grade and post-operative chemotherapy increased risk of death. However, resection of the primary tumor along with liver metastasis improves the 5-year OS with complete cytoreduction providing the most benefit.
Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary. | 2017 ASCO Annual Meeting Abstracts
Conclusions: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (pNETs, merkel cell and pheochromocytoma).
Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NET. The NETest accurately measures the effectiveness of treatment.
Conclusions: Grade 3 GEP-NECs could be morphologically classified into well and poorly differentiated NETs. Additionally, among grade 3 GEP-NECs, there was a significant difference in ranges of Ki67 index between well and poorly differentiated NECs. Higher levels ( > 60%) of Ki67 index might be a predictive marker for efficacy of EP as a standard regimen in grade 3 GEP-NECs.
Check out my blog post on Gradingwhich has incorporated latest thinking in revised grade 3 classification
Seung Tae Kim
Theranostic trial of well differentiated neuroendocrine tumors (NETs) with somatostatin antagonists 68Ga-OPS202 and 177Lu-OPS201.
Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of 68Ga-OPS202/177Lu-OPS201 as a theranostic combination for imaging and therapy. Additional studies are planned to determine an optimal therapeutic dose and schedule. Clinical trial information: NCT02609737
Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.
Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach and this highly targeted patient therapy may significantly improve treatment of tumors that over express somatostatin receptor.
I spend a lot of time talking about the most common forms of Neuroendocrine Tumours (NETs), but what about the less well-known types? As part of my commitment to all types of NETs, I’d like to shine a light on two less common tumour types known as Pheochromocytomas and Paragangliomas – incidence rate approximately 8 per million per year. They are normally grouped together and the definitions below will confirm why. If you think it’s difficult to diagnose a mainstream NET, this particular sub-type is a real challenge.
So, let’s get definitions out of the way:
Pheochromocytomas (Pheo for short)
Pheochromocytomas are tumours of the adrenal gland that produce excess adrenaline. They arise from the central portion of the adrenal gland, which is called the adrenal medulla (the remainder of the gland is known as the cortex which performs a different role and can be associated with a different tumour type). The adrenal medulla is responsible for the normal production of adrenaline, which our body requires to help maintain blood pressure and to help cope with stressful situations. The adrenal glands are situated on top of the kidneys (i.e. there are two). Adrenaline is also called ‘epinephrine’ which is curiously one of the 5 E’s of Carcinoid Syndrome.
Paragangliomas (Para for short)
Paragangliomas are tumours that grow in cells of the ‘peripheral’ nervous system (i.e. the nerves outside the brain and spinal cord). Like Pheochromocytomas, they can release excess adrenaline. There can be confusion between the two types of tumour as Paragangliomas are often described as extra-adrenal Pheochromocytomas (i.e. a Pheo external to the adrenal gland).
Going forward, I’m going to talk about both using the single term of ‘Pheochromocytoma’ in the context of an adrenaline secreting tumour but may refer to Paraganglioma where there might be a difference other than anatomical location.
Pheochromocytomas are often referred to as the “ten percent tumour” because as a rule of thumb they do many things about ten percent of the time. However, these figures are slowly changing, so this label is gradually becoming less apparent. The following is a fairly exhaustive list of these characteristics:
A few facts about Pheochromocytomas
As much as 1 in 3 are Malignant but most have undetermined biologic potential. A recent document issued by the World Health Organisation (WHO) stated that “Paragangliomas should not be termed benign”.
Around 10% of Pheochromocytomas are Bilateral (i.e. found in both adrenal glands: 90% arise in just one of the two adrenal glands)
Around 10% are Extra-Adrenal (found within nervous tissue outside of the adrenal glands … i.e. 10% are Paragangliomas)
Around 10% are found in Children (i.e. 90% in adults)
Up to 30% are Familial potentially rising to 50% for metastatic cases and Multiple Endocrine Neoplasia (MEN) involvement.
The recurrence rate is around 16%, i.e. about 1 in 6 patients have a tumor that comes back after surgery. Tumors that come back also have the potential to be malignant. If you have pheo or para and have surgery to remove it, be sure to continue to check in with your doctor to monitor for any returning tumors.
Present with a stroke (10% of these tumours are found after the patient has a stroke)
The classic symptoms of Pheochromocytomas are those attributable to excess adrenaline production. Often these patients will have recurring episodes of sweating, headache, and a feeling of high anxiety.
Headaches (severe)(one of the classic triad, see below)
Excess sweating (generalized)(one of the classic triad, see below)
Racing heart (tachycardia and palpitations)(one of the classic triad, see below)
Anxiety and nervousness
Nervous shaking (tremors)
Pain in the lower chest or upper abdomen
Nausea (with or without vomiting)
According to the ISI Book on NETs (Woltering, Vinik, O’Dorisio, et al), Pheochromocytomas present with a classic triad of symptoms and signs: headache, palpitations and sweating. This symptom complex has a high specificity and sensitivity (>90%) for the diagnosis of Pheochromocytomas. The figure is much lower in individual symptom presentations (palpitations 50%, sweating 30%, headaches 20%). In addition to correctly diagnosing from these symptoms, Pheochromocytomas may also be found incidentally during a surgical procedure even after a diagnosis of an ‘adrenal incidentaloma’
Markers. Like serotoninsecreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured by 24 hour urine test very similar to 5HIAA (with its own diet and drug restrictions). It’s known as 24-hour urinary catacholamines and metanephrines. This test is designed to measure production of the different types of adrenaline compounds that the adrenal glands make. Since the body gets rid of these hormones in the urine, we simply collect a patient’s urine for 24 hours to determine if they are over-produced. Like 5HIAA, there is also a plasma (blood draw) version of the test. According to the ISI Book on NETs, there is also an additional test called ‘Vanillylmandelic Acid (VMA). This reference also indicates the most sensitive test is plasma free total metanephrines. Also read more here.
Genetics. The familial connection with Pheo/Para is complex. Up to 13 genes have been identified including NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2(SDH5), TMEM127, MAXm EPAS1, FH, MDH2. Read more here ( recent update). The NIH also have a useful section –click here.
Scans. Other than the usual range of scanners, ultrasound, CT/MRI, all of which may be used to find evidence of something, the other scan of note is called MIBG. This is a nuclear scan similar in concept to the Octreotide Scan given to many NET patients (in fact some Pheo patients my get an Octreotide scan if they have somatostatin receptors). The key differences with MIBG is the liquid radioactive material mix which is called iodine-123-meta-iodobenzylguanidine or 131-meta-iodobenzylguanidine (this is where the acronym MIBG originates). Together with the markers above, the results will drive treatment. Depending on availability, the latest PET scans may also be available potentially offering greater detail and accuracy i.e. 18F-FDOPA, 18F-FDG and Ga68. Read more on scans here.
This statement and diagram was provided by Dr Mark Lewis who is an Oncologist and MEN patient. “The algorithm for working up a hyperadrenergic state is attached (and was developed by Dr. Young at Mayo Clinic). It outlines the most reliable testing for a pheo or Paraganglioma”
Additional Factors and Considerations
This is an awareness post so I’m not covering treatment options in any detail except to say that surgery if often used to remove as much tumour as possible. Somatostatin Analogues may also be used in certain scenarios in addition to other hormone suppression or symptom controlling drugs. That said, Pheo/Para patients may be interested in a PRRT trial exclusively for Pheo/Para – read more here (see section entitled – “What about Pheo/Para”)
The adrenal cortex mentioned above is actually the site for Adrenocortical Carcinoma (ACC) – this is a totally different cancer.
Pheochromocytomas are probably difficult to diagnose (you only have to look at the symptoms to see that). The differential diagnoses (i.e. potential misdiagnoses) are: hyperthyroidism, hypoglycaemia, mastocytosis, carcinoid syndrome, menopause, heart failure, arrhythmias, migraine, epilepsy, porphyria lead poisoning, panic attacks and fictitious disorders such as the use of cocaine and benzedrine.
Many Pheochromocytoma patients will also be affected by Multiple Endocrine Neoplasia (MEN), in particular MEN2 (there are some wide-ranging percentage figures online for this aspect). There can also be an association with Von Hippel-Lindau (VHL) syndrome and lesscommonly with Neurofibromatosis type 1.
Given the nature of the hormones involved with Pheochromocytomas, there is a risk of intraoperative hypertensive crises. This is similar in some ways to Carcinoid Crisis but needs careful consideration by those involved in any invasive procedure.
Newly Approved Drug – AZEDRA
On 30th July 2018, Progenics Pharmaceuticals Announces FDA Approval for AZEDRA® (iobenguane I 131) to Treat Unresectable, Locally Advanced or Metastatic Pheochromocytoma or Paraganglioma – read more by clicking here.
Pheochromocytomas are very complex involving many of the challenges found in the more abundant and common types of NETs. To underscore this statement, please see this case studywhere one patient was misdiagnosed with psychiatric problems for 13 years before being correctly diagnosed with a metastatic Pheochromocytoma.
This is an extremely basic overview offered as an awareness message about the lesser known types of NETs. I refer you to my disclaimer. If you wish to learn more about Pheochromocytomas and Paragangliomas, check out the links below.
Just a note to say Happy Thanksgiving to my friends in USA or who may be celebrating it elsewhere. I am so thankful for the support I get from the US who make up the biggest proportion of subscribers to my blog and associated Facebook page. So I’m thinking of y’all today!
Now …….. I hate to stereotype but I guess a lot of you might be eating turkey today? No Thanksgiving is complete without a turkey at the table (… so I’m told!). And also a nap right after it’s eaten….. right?
As you know I like to analyse such things …… Apparently, the meat has a bad reputation for making eaters sleepy, but is there really science to back that up? My google alerts feed increases around this time of the year due to the connection of turkey with the word ‘serotonin’. So for me, this is very educational. Those who read my blog article on the ‘S’ word may remember that tryptophan is one of the bodies amino acids and is partly responsible for the manufacture of Serotonin in our system. Turkey is said to be high in tryptophan although most say it is no higher than many other meats. I’ve also heard the stories about how eating too much turkey makes you sleepy. Melatonin is said to be the hormone which helps with sleep regulation and is manufactured from Serotonin (which is manufactured from tryptophan). However, the articles I read, (one was from the New York Times and one from Time Magazine) both confirm this is not exactly correct with one describing the turkey/sleepy connection as a “common myth” mainly due to the other food and drink consumed at the same time as the turkey In any case, what’s wrong with an afternoon or evening nap after a traditional meal?
For those worried about eating too much tryptophan, don’t be, all NET nutritionists say you should not be concerned about this and the only food restrictions that apply are right before the 5HIAA test as directed by your local specialist.
Actually I read that turkey is a really healthy meat to eat, it’s low in fat, full of protein and other nutrients including the important B vitamins that NET patients might be at risk of deficiency (B3 and B12). Note to self …… eat more turkey!
Enjoy your Thanksgiving! It’s OK to have a nap too ……
On a personal note, I’m also very thankful to still be here after 8 years!
When you’ve been diagnosed with cancer at an incurable stage, certain words start to mean more. Take ‘palliative’ for example. Before I was diagnosed I had always associated the word ‘palliative’ with someone who had a terminal disease and this type of care was to make the final days/weeks as comfortable as possible. So it was a bit of a shock to find out in 2010 that my treatment was palliative in nature. However, I’m still not dead and I’m still receiving palliative care. Go figure! The answer is simple – the cancer story is changing. What was once feared as a death sentence is now an illness that many people survive. As survival rates increase, so too will the number of people living with the legacy of cancer and its treatment.
What is palliative care?
Some people with incurable cancer will continue to receive treatment to keep the cancer at bay and that treatment is by definition, palliative. In fact, palliative care can be given at any time during an illness. It’s not just for treatment of the cancer, it’s also to help with the effects of that treatment, i.e. the consequences of cancer. It also encompasses things such as emotional and other practical support.
In the most general terms and while it clearly can go into some detail and long lists, palliative care can be defined as follows:
Cancer and its treatment often cause side effects. Relieving a person’s symptoms and side effects is an important part of cancer care. This approach is called symptom management, supportive care, or palliative care. Palliative care is any treatment that focuses on reducing symptoms, improving quality of life, and supporting patients and their families. Any person, regardless of age or type and stage of cancer, may receive palliative care.
I looked at a few sites and many of them confirm the above. However, there appears to be even more sites where it is still heavily associated and inextricably linked with end of life or hospice care where you may come into contact with the term palliative care specialist. Whilst it’s not wrong to make that association, more work needs to be done to cater for the growing numbers of ‘incurable but treatable’ who are not ‘terminal’ and still need this type of support, in some ways like you would with a chronic condition. I also sense a push in certain areas to emphasise the meaning of palliative care to include a much broader definition than is currently in most people’s minds. This needs much more publicity. I’m not saying that ‘palliative’ does not include ‘hospice care’ but I’m not intending to cover that aspect in this blog which is aimed as those with incurable but treatable cancers.
My palliative care experience
When I was diagnosed with metastatic Neuroendocrine Tumours (NETs) in 2010, I quickly accepted the fact that any treatment I would receive would not be curative. I also quickly accepted that if I didn’t have any treatment, I would probably die. The words used were ‘debulking’ and ‘cytoreductive’, more technical sounding but essentially meaning the same thing as palliative. Debulking means removing as much tumour as possible in order to increase the chance that perhaps other treatments can be of some help. Cytoreductive means the same thing but generally extends the ‘debulking’ activity to other modes of treatment (e.g. chemotherapy/radiotherapy).
NETs is one of a number of cancers for which ‘debulking’ and ‘cytoreductive’ therapies can in many cases confer some survival advantage. In fact if you read ENETS or NANETS guidance for advanced NETs, you will frequently see the statement that cytoreductive surgery should be considered if greater than 90% of metastatic tumour burden can be safely resected or ablated. NETs, particularly with distant metastases, can come with a ‘syndrome’ and some of the symptoms can be rather debilitating for many patients. These syndromes are a result of tumours secreting excess amounts of hormonesand the types vary from patient to patient and from NET type to NET type. It follows that if surgical debulking reduces the amount of tumours, then it should normally decrease the effects of the associated syndrome. In fact, one letter from a specialist did describe my surgery in symptom palliation terms. I can confirm this is about right as my hormone marker 5HIAA remained elevated after surgery to remove my primary and local tumours, but did not return to normal until after my liver surgery.
However, there are a number of other treatments that can be considered ‘palliative’ in a metastatic or advanced environment. Getting rid of tumours is always the optimum treatment for any cancer but just as surgical debulking can reduce the amount of cancer, other non-surgical modalities such as liver embolization or ablation can have the effect of reducing the symptoms of the cancer and therefore providing relief to the patient. Somatostatin Analogues (Octreotide/Lanreotide) are another good example of palliative care. Although they might have an anti-tumour effect for some, they mostly work by reducing or inhibiting the secretion of excess hormones which contribute to the various NET syndromes. ‘Symptom control’ is as defined above, palliative care.
I’m already looking forward to my next palliative care appointment.
Diarrhea can be a symptom of many conditions but it is particularly key in Neuroendocrine Tumour (NET) Syndromesand types, in particular, Carcinoid Syndrome but also in those associated with various other NET types such as VIPoma, PPoma, Gastrinoma, Somatostatinoma, Medullary Thyroid Carcinoma.
Secondly, it can be a key consequence (side effect) of the treatment for Neuroendocrine Tumours and Carcinomas, in particular following surgery where various bits of the gastrointestinal tract are excised to remove and/or debulk tumour load.
There are other reasons that might be causing or contributing, including (but not limited to) endocrine problems such as hyperthryoidism, mastocytosis or Addison’s disease (which may be secondary illnesses in those with NETs). It’s also possible that ‘non-sydromic’ issues such as stress and diet are contributing. It could be caused by other things such as Irritable Bowel Syndrome (IBS). Yes, believe it or not, NET Patients can get normal diarrhea causing diseases too!
I want to give a general definition of diarrhea as there are many variants out there. In general, they all tend to agree that diarrhea is having more frequent, loose and watery stools. Three or more stools per day seems to be the generally accepted threshold, although some sites don’t put a figure on it. It’s not pleasant and just about everyone on the planet will suffer it at some point in their life, perhaps with repeated episodes. Normally it’s related to some kind of bug, or something you’ve eaten and will only last a few days before it settles (acute diarrhea). Diarrhea lasting more than a couple of weeks is considered chronic and some people will require medical care to treat it. It can also be caused by anxiety, a food allergy/intolerance or as a side effect of medicine. Pharmacists and GPs will be seeing many patients with this common ailment every single day of business.
Diarrhea induced by a Syndrome
When you consider the explanation above, it’s not really surprising that diarrhea related symptoms can delay a diagnosis of Neuroendocrine Cancer (and most likely other cancers too, e.g. pancreatic cancer, bowel cancer). For example, diarrhea is the second most common symptom of Carcinoid Syndrome (Flushing is actually the most common) and is caused mainly by the oversecretion of the hormone Serotonin from the tumours. Please note diarrhea in other types of syndromes or NETs may be caused by other hormones, for example it may also be caused by excess calcitonin in the case of Medullary Thyroid Carcinoma or VIP in the case of a functional pNET known as VIPoma. I’ve heard stories of people being told they have IBS or something similar for years before they received what is now a late diagnosis and at an advanced cancer stage. This is only one of the reasons why NETs is not an easy condition to diagnose, although it is possible that some people actually had IBS and it was masking the NET. Even after treatment to remove or reduce tumours, many people will remain syndromic and need assistance and treatment to combat diarrhea induced by a NET syndrome (see below).
Diarrhea as a Consequence (Side effect) of Treatment for Neuroendocrine Cancer and Other Conditions
All cancer treatments can have consequences and Neuroendocrine Cancer is definitely no exception here. For example, if they chop out several feet of small intestine, a chunk of your large intestine, chunks (or all) of your stomach or your pancreas, your gallbladder and bits of your liver, this is going to have an effect on the efficiency of your ‘waste disposal system’. One effect is that it will now work faster! Another is that the less effective ‘plumbing’ may not be as efficient as it was before. There are also knock-on effects which may create additional issues with the digestive system including but not limited to; Malabsorption and SIBO. I recommend you read my posts on Malabsorption and SIBO.
Surgery can often be the root cause of diarrhea. A shorter gut for example, means shorter transit times presenting as increased frequency of bowel movements. Another example is the lack of terminal ileum can induce Bile Acids Malabsorption (BAM) (sometimes known as Bile Salts Malabsorption) in degrees of severity based on size of resection. Lack of a gallbladder (common with NETs) can also complicate. Bile Acids are produced in the liver and have major roles in the absorption of lipids in the small intestine. Following a terminal ileum resection which includes a right hemicolectomy, there is a risk that excess Bile Acids will leak into the large intestine (colon) via the anastomosis (the new joint between small and large intestines). This leakage can lead to increased motility, shortening the colonic transit time, and so producing watery diarrhea (or exacerbating an existing condition). Although this condition can be treated using bile acid sequestrants (i.e. Questran), it can be difficult to pinpoint it as the cause.
Surgery of the pancreas can also produce effects such as exocrine pancreatic insufficiency which can lead to a malabsorption condition known as steatorrhea which may be confused with diarrhea (although some texts call it a type of diarrhea). It isn’t really diarrhea but it may look like it given the presentation of the faeces and patients may suffer both diarrhea and steatorrhea concurrently. Patients will recognise it in their stools which may be floating, foul-smelling, greasy (oily) and frothy looking. Treatment options will mainly include the use of Pancreatic Enzyme Replacement Therapy or PERT for short (Creon etc).
Many non-surgical treatments can also cause diarrhea, including but not limited to; somatostatin analogues (see below), chemotherapy, biological targeted therapy (e.g. Everolimus, Sunitinib), radiotherapy.
Somatostatin analogues are an interesting one as they are designed to inhibit secretion of particular hormones and peptides by binding to the receptors found on Neuroendocrine tumour cells. This has the knock-on effect of inhibiting digestive/pancreatic enzymes which are necessary to break down the fat in our foods leading to Malabsorption of important nutrients. This may worsen the steatorrhea in pancreatic NET patients but also lead to steatorrhea in others with non-pancreatic locations who have been prescribed these drugs.
Other conditions may actually be the cause of the diarrhea or the treatment for those conditions. For example, it is possible that people actually do have Irritable Bowel Syndrome (IBS). Treatment therapy for common conditions may also be contributing, for example the use of Proton Pump Inhibitors for acid reflux.
Treatment for Syndrome Induced Diarrhea
Like many other NET patients, I’m on a 28 day injection of somatostatin analogues (in my case Lanreotide). Both Octreotide and Lanreotide are designed to reduce the effects of NET syndromes and therefore can often make a difference to syndrome induced diarrhea. These drugs also have anti-tumour effect and so even if you are not syndromic or they do not halt or adequately control syndrome induced diarrhea, they are still a valuable contribution to NET treatment.
Some syndromic patients find they still have diarrhea despite somatostatin analogues and they end up having ‘rescue shots’ or pumps for relief (both of these methods tend to be Octreotide based). (Hopefully they are not getting confused between diarrhea caused by the non-syndrome effects – see above). Some have more frequent injections of the long acting versions of somatostatin analogues which has the effect of increasing the dosage. There’s a new drug available for those whose carcinoid syndrome induced diarrhea is not adequately controlled or perhaps they are unable to have somatostatin analogues as a treatment. Telotristat Ethylworks by inhibiting tryptophan hydroxylase (TPH), a chemical reactor involved in the manufacture of serotonin, which is the main cause of syndrome induced diarrhea. It was approved by the US FDA in February 2017, EU areas in September 2017, and is on the way to being approved elsewhere. Read about this drug here.
Sorting out the symptoms – post diagnosis
I like to describe this as the Neuroendocrine Cancer jigsaw. It’s a really difficult one and sometimes you cannot find a piece, or the pieces won’t fit. However, metaphorically speaking, the missing piece might be a NET specialist presentation, a comment, statement or view from another patient, a link to an article from a reputable source, or even something you do to improve your lot – there might even be trial and error involved. It might even be this blog post!
How do you work out whether diarrhea is caused by a hormone producing tumour or by the side effects of treatments? There’s no easy answer to this as both might be contributing. One crude but logical way is to just accept that if you have normal hormonemarkers, for example 5HIAA (there could be more for other tumour/syndrome types), and you’re not really experiencing any of the other classic symptoms, then your syndrome might be under control due to your treatment (e.g. debulking surgery and/or somatostatin analogues, or another drug). My Oncologist labels me as ‘non-syndromic’ – something which I agree with. I’m 99.999999% sure my issues are as a result of the treatment I’ve had and am receiving.
This disease is so individual and there are many factors involved including the type of syndrome/NET, patient comorbidities and secondary illnesses, consequences of the surgery or treatments performed, side effects of drugs – all of which is intermingled with suspicion and coincidence – it’s that jigsaw again! I always like to look in more detail to understand why certain things might be better than others, I always challenge the ‘status quo’ looking to find a better ‘normal’. I really do think there are different strategies for syndrome induced diarrhea and that which is a result of treatment or a side effect of treatment. There’s also different prices, with inhibitors costing thousands, whilst classic anti-diarrhea treatments are just a few pennies. Adjustments to diets are free!
When I was discharged from hospital after the removal of my small intestinal primary, I was in the toilet A LOT (I was actually in the toilet a lot before I was discharged – check out my primary surgery blogs here) . My surgeon did say it would take months to get back to ‘normal’ – he was right and it did eventually settle – although my new ‘toilet normal’ was soft and loose and several times daily. My previously elevated CgA and 5HIAA were eventually back to normal and my flushing had disappeared. I didn’t have too many issues with diarrhea before diagnosis. Deduction: my issues are most likely not syndrome induced.
I read that many people find basic ‘Loperamide’ (Imodium) helps and I tend to agree with that if you are non syndromic and just need that little bit of help. I decided long time ago I would not become ‘hooked’ and only really take it for two purposes: 1) if I have a bad patch and 2) if I’m going on a long journey (i.e. on a plane perhaps). I estimate I’ve used 4 packets in as many years. Loperamide decreases the activity which causes intestinal motility (peristalsis). This has the effect of increasing the time material stays in the intestine therefore allowing more water to be absorbed from the fecal matter. Ideal for those with a shorter bowel due to surgery and advice from a medical professional is always advisable. To reduce the risk of malabsorption induced diarrhea and steatorrhoea, both of which can lead to loss of valuable nutrients, the use of Pancreatic Enzyme Replacement Therapy (PERT) might need to be introduced as required by your NET specialist.
Have a look at Enterade – the results from trials look good.
Clearly, I cannot offer any professional medical advice on coping with diarrhea, I can only discuss my own situation and what I found worked for me. Don’t forget, like many diseases, what works for one, might not work for another. However, I did tackle my problems following the advice of an experienced dietitian who specialises in NET Cancer. That said, I was ‘sleep walking’ for over 2 years thinking my issues were just part of the way things were after my treatment. I was wrong about that!
As for my own strategy, here’s things that helped me:
made some changes to diet(they were not huge changes),
maintained a diary to help with monitoring progress or setbacks,
hydration is also important (….still working on that one).
started taking PERT (Creon) on 23 Dec 2017 (changed to Nutrizym Feb 2019) but looks reasonably positive so far.
With no fancy and expensive drugs, I’ve gone from 6-8 visits to 1-2 visits (as a daily average, it’s actually 1.5). This didn’t happen overnight though, it took a lot of time and patience. All of this doesn’t mean to say I don’t have issues from time to time …… because I do!
In summary, I think it’s important that people be sure what is actually causing their diarrhea after diagnosis so that the right advice and the optimum treatment can be given.
Listen to Dr Wolin talking about this particular jigsaw puzzle – click here
Also see a nice article that come out of NANETS 2017 – click here
Of course, some people sometimes have the opposite effect but that’s in another blog here – Constipation
Since my diagnosis, I seem to have been in a perpetual learning phase! What not to do, what not to eat, what not to read! However, early on in my experience, I came across a list of ‘E’ words (5 of them) which is a handy reminder for Carcinoid Syndrome patients, particularly those whose symptoms are not under control. When I say “carcinoid syndrome” in this article, I only mean the syndrome that is caused by what was once called “Carcinoid Tumors”, i.e. mainly serotonin secreting types but include tumours which are well differentiated found in the small intestine, appendiceal, rectal, lung, and one or two other less common places. There are many variations of this list but this is my take! I suspect some of this also applies to other types of NETs and other NET Syndromes.
On analysis of this list, it struck me that I was aware of the issues and their potential effects and I’m certain there is science to substantiate the content. These E’s are apparently the most common ‘triggers’ for Carcinoid Syndrome. Clearly, they are not going to have the same effect on every patient e.g. I have the occasional drink of ‘Ethanol’ and I always enjoy it, I go for long exhausting walks as ‘Exercise’ and I always feel great after. I had dental treatment using ‘Epinephrine’ without any precautions before I was aware of the risks …….. nothing happened! Before I was treated, stressful meetings (‘Emotions’) at work would make me flush though! As for ‘Eating’ – well that’s another couple of blog’s worth! Worth noting that many people without carcinoid syndrome will have reactions to eating but there are specifics that might need some attention in someone with carcinoid syndrome and elevated 5HIAA levels.
The 5 Es are, however, not something to be totally ignored. In extreme scenarios, a severe attack of Carcinoid Syndrome symptoms could be debilitating and life-threatening and I’m fairly certain the list was compiled with this in mind. Some people are more affected by Carcinoid Syndrome and this is not necessarily related to the extent or aggressiveness of their disease. Some people just react differently. An extremely severe attack of Carcinoid Syndrome can also be known as a ‘Carcinoid Crisis’ which is very dangerous, mostly on the operating table due to the effects of anaesthetics – thus why many NET patients may be infused with somatostatin analogues (usually Octreotide) prior to, during, and for a period after surgery or other medical procedures. There’s a lot of excitement generated around the term ‘Carcinoid Crisis’ but it is very uncommon.
I’m not saying the 5 Es should be ignored but NETs are a complex disease and most things need to be read in the correct context. What works for some may not work for others. There can also be confusion surrounding the source of symptoms, i.e. are they syndrome or something else? This is why I believe NET patients need to answer some key questions when considering the risks associated with the 5 E’s:
Are you currently syndromic? If you are, then the 5 ‘E’ list is probably very good advice but interpreting the advice in the correct context remains important.
Are your syndrome related biochemistry results normal (e.g. 5HIAA)? Normal readings (in range) tend to mean the syndrome is under control and many people who were diagnosed with a syndrome may actually be non-syndromic following treatment.
Have you had treatment or are having treatment likely to produce side effects which might be confused with Carcinoid syndrome? For example, surgery can be the long term cause of diarrhea and other issues. Despite the role of somatostatin analogues, these could also be the root cause of certain reactions.
The vagaries of this disease will no doubt throw up some exceptions and additions. There will be patients who have no syndrome but have elevated biochemistry and vice versa. Additionally, there will be patients who have had surgery and/or are being treated with somatostatin analogues but will still be syndromic in varying degrees of severity.
The so-called ‘5 Es’ are as follows:
Epinephrine: This was a new piece of information for me and I only discovered this as a potential problem when I started monitoring some of the USA Facebook forums. This does not appear to be that well-known in UK.
Epinephrine (commonly known as adrenaline) is often used in dentistry mixed with a local anaesthetic. I won’t risk this, so I’ve instructed my Dentist to place a note on my record asking for epinephrine not be used (and clearly I’ll remind them each visit!). According to NET guru Dr Woltering, plain novocaine, carbocaine or plain marcaine are preferred. According to a dental source on my site (also a patient):
“4% Citanest Plain Dental (Prilocaine Hyrocholride Injection) is also safe and Epinephrine Free. It isn’t as profound of a numbness and may need reapplying during a procedure. It is the common alternative here in the USA.
4% Articaine without Epinephrine is also available and is known to work better on Mandibular Blocks. Again this is commonly used in the USA. It’s important to know what to ask for, not just ‘Epinephrine free’. Bring this up at your dental exam appointment, so that they will be sure to have it in stock. If you are unfamiliar with the office, schedule your appointment after they confirm that the proper local is in stock. Never use the term Novacaine as the generic term for dental anesthetic, this hasn’t been used in the USA for decades. Allergic reactions to Novacaine were too common. Lidocaine and Septocaine are the drug of choice. However, Lidocaine will always have Epinephrine. Where as, Septocaine (articaine) has versions with Ephedrine and without”.
Always check that your anaesthetist for any procedure you may be undergoing is aware of your carcinoid syndrome.
However, the danger is not just with dentistry work. Any anaesthesia is risky. Check out my post ‘carcinoid crisis’.
For those who have standby ‘Epi Pens’, I did read the following statement on the Carcinoid Cancer Foundation website: “ …….. one exception is the administration of epinephrine in the case of an allergic anaphylactic reaction (i.e. a bee sting), so it cannot be avoided in this case, just make sure that Octreotide (Sandostatin) is also available“. This advice is also extremely relevant to Pheochromocytoma and Paraganglioma patients who may be a high risk of “intraoperative hypertensive crisis”.
Eating: This is very individual. Certain foods or large meals can be difficult, particularly if you have had any gastrointestinal surgeries. I keep a personal diary trying to identify things that upset my system. I try to find some balance between what I know is good for me and also what I know I enjoy. For example, I found that very large meals do not agree with my ‘new plumbing’. If I eat a lot of sweets, I’ll also suffer …..so I just eat a little – check out my article Chocolate – The NET Effect.
Personally speaking, I’m fairly certain the vast majority of my issues are related to my treatment (past and present) rather than being provoked by Carcinoid Syndrome, i.e. if I rush to the toilet after a meal, it’s not syndrome, it’s a reaction of my compromised digestive system. So with this in mind, I try to reduce those things but additionally strike a balance between quality of life and excessive and rigid adherence to some of the guidance out there (see below) – as I said above, interpretation and context is important. My compromised system cannot deal with big meals so I ‘graze’ most of the day and then eat a small to medium-sized meal in the evening. I’ve been doing this since 2014 and reduced my visits by 300% without any special or expensive medication.
In my blog Nutrition Blog 4 – Food for Thought, I’ve linked to authoritative sources on potential diet triggers. I’m not suggesting you cut out all of the foods on these lists (you won’t last long!). Some can indulge in those foods and some cannot. For example, chocolate and caffeine (tea/coffee) are on the lists but I eat/drink those frequently (in moderation) and have no problem. It’s a case of testing things out. I like to describe my eating as ‘The Risk Management of my Quality of Life’. By the way, no-one is suggesting that a NET patient with carcinoid syndrome (and don’t forget this is only one syndrome of many with NETs) should stop eating foods high in the offending amines or are precursors to serotonin (e.g. tryptophan). They do not make tumours grow (a myth) but just make sure you adhere to the dietary restrictions for any 5HIAA test.
Emotions: Stressful situations can cause symptoms to flare up. While it is difficult to avoid all stress (work, home, commuting, etc), it is helpful if you can manage or reduce it. Like eating, this is a very individual area. From personal experience, I know stress can exacerbate carcinoid syndrome. Before I started my treatment, I was regularly flushing in meetings at work (….. think boxing matches!). After my treatment, stress was definitely a factor causing increased bowel motility. I’ve removed a lot of stress from my life and it helps. You may need to be ruthless in managing this aspect of your illness.
Exercise: Exercise is extremely important for overall health and well-being and I know quite a lot of NET Cancer patients who exercise regularly without issues. It can, however, trigger carcinoid syndrome if you overdo it – it is, however, like eating, a very individual thing. I take the view that ‘zero’ exercise might potentially be an even higher risk. Even a walk around the garden or gardening is exercise. When I was at work, I would walk to see people rather than phone them. Sometimes I walk to town rather than drive, it all adds up! I have evidence from my own exercising regime proving in my case that exercise can reduce the knock-on effects of some of the other E’s (emotions and eating) and/or the side effects of treatment – check out my blog entitled Exercise is Medicine. Those who are syndromic and/or have other conditions to manage are probably best to take medical advice on how much exercise they need to do.
Ethanol (alcohol, liquor):Many NET patients have difficulty tolerating wine, beer and spirits (hard liquor). I was never a big drinker so for me it was easy to go almost teetotal. I do have the occasional beer but very infrequently and normally on holiday – I personally don’t get any issues with the odd beer but again this is trial and error. I really enjoy my beer when I celebrate my ‘Cancerversaries‘. Also check out my blog Alcohol – the NET Effect
I’m sure there could be a 5 A’s to 5 Z’s list of things to avoid but as I said above, this needs to be balanced with what the actual risks for you are and if you’re like me, quality of life. If you read most Facebook closed group or forums, you will always find at least one person is affected by something which affects no-one else. Please note this article is just my own appreciation of these issues and I emphasise once again that everyone has different experiences. I do, however, think it’s important to consider any secondary illnesses, effects of surgery and biochemistry results (or indeed a combination of one or more of these factors). Everything in life involves some kind of risk management and if you are totally risk averse, then you are unlikely to have much of a life (or a diet!).
It’s not easy but my daily diary helps me assess trends and work out what things upset me more than others – I can then reduce or eliminate. You need to tailor your own advice perhaps with the help of a doctor and/or dietician versed in NET Cancer. I also have some related posts on the subject of vitamin and mineral deficiencies, malabsorption and probiotics – check them out as the problems associated with these subjects could potentially look like a worsening of carcinoid syndrome and lead to unnecessary worry and unnecessary treatment.
For most, Carcinoid Syndrome can normally be controlled by the use of debulking surgery and/or somatostatin analogues (Octreotide/Lanreotide). However, there is a new drug called ‘Teloristat Ethyl’ (XERMELO) which looks like it may provide supplementary treatment for patients whose carcinoid syndrome diarrhea is not adequately controlled by somatostatin analogues. It’s an expensive drug and comes with side effects so you need to be sure it’s your syndrome causing the problem before you commit to a prescription.
From day 1 of my diagnosis, I knew my liver was going to need some attention but I had always known that total removal of all tumours would not be possible. This critical organ did in fact produce the biopsy confirming Neuroendocrine Cancer. The early scans indicated multiple liver lesions and an Octreotide scan reported several quite avid isotope activity.
However, as you can see from my clinical history, they first stabilised my syndrome via daily Octreotide so my tumours were subdued ready for major surgery ’round 1′ which took place Nov 2010 – I wrote about this as Part 1 and Part 2 stories. As we are talking about my liver, it’s worth noting that a bland Liver Embolization was carried out prior to ’round 1′ as there was an option to look at the liver whilst I was ‘open’. However, after 9 hours sorting out my other areas, there was insufficient time.
My surgeon (Mr Neil Pearce) promised me a hard year so after 4 months ‘rest’, I was brought back in for major liver surgery (round 2) which took place on 12 Apr 2011. The ‘luck’ word has to be mentioned again because my local NET MDT was led by Mr Pearce who just happened to be one of UK’s top GI surgeons and one of the pioneers of Laparoscopic surgery – that is what I was to receive. In the end, I had a right hepatectomy and a metastasectomy which was calculated to be approximately 66% of my liver removed. Thank goodness it grows back!
The operation went well lasting 6 hours although it could have been shorter. Mr Pearce unfortunately had to spend a quarter of this time picking through ‘dense right sided abdominal adhesions’ caused by ’round 1′. My liver metastasis was described as significant on inspection and around 90% of the tumours were removed during this procedure leaving around half a dozen sub-centimetre deposits. Interestingly he said my pattern of disease was more conspicious on intra-abdominal ultrasound than it had been on previous scans. You can see from the post picture, the type of instruments used in laparoscopic surgery and the fact that they pump air into the abdomen to give sufficient space to operate.
I recovered quickly after only 5 days in hospital and was back at work in 3 weeks. My Chromogranin A finally returned to normal readings recognising the reduction in tumour bulk. My 5HIAA was already back in normal after ’round 1′ and subsequent commencement of Lanreotide. For those who have not had a liver laparoscopic procedure, the healing time is much quicker and you only have limited scarring. I had 3 ‘stab wounds’ (that’s my name for the marks!) across the area of my liver and then a 3 inch scar at the base of my abdomen which was used to remove the ‘bits’ of resected liver.
A follow-up chemo-embolization or TACE (Trans Arterial Chemo embolization) was scheduled a few weeks after the liver surgery which was looking to target the remnant liver tumours. However, this had to be aborted following some routing issues caused by ’round 1′ surgery.
I still have some residual (but stable) disease on my liver but there has been no progression in these 6 years. It’s no secret that debulking or cyto-reductive surgery can be of benefit even to those with advanced or metastatic well differentiated Neuroendocrine disease. I remain thankful for the care and attention I received in the months after my diagnosis.
Please note a new syringe for Lanreotide will be available in 2019, at least in Ireland and UK which have confirmed dates (UK is end of June rollout begins). However, Ipsen are committed to roll it out to the rest of Europe, US, Canada, Australia and New Zealand by end of 2019 (details to follow) following necessary regulatory approvals.
Further information will be communicated to healthcare professionals in advance of this, to enable them to inform their patients, whom have been prescribed Lanreotide. In addition, the patient information leaflet included in the packet will have clear instructions for use. There will be a prominent yellow box located on the outer carton of the medicine, alerting healthcare professionals and patients that a new syringe is contained inside.
The new pre-filled syringe for Somatuline® Autogel® was the result of several studies, involving patients, their caregivers, nurses and other healthcare professionals, to inform and test enhancements to the existing pre-filled syringe. Notable new features are modified ergonomics and handling, a needle shield removal system, an injection process with plunger support and heightened ease of use. The automatic, built-in safety system, which helps to prevent needle stick injury by locking in place following the administration, has not been changed.
Please note that the medicine is still the same and the formulation and storage conditions have not changed.
The picture below is the new injection inside its protective case.
My Lanreotide Experience
When I was discharged from hospital following major surgery in Nov 2010, I knew I would shortly be commencing long-term monthly ‘somatostatin analogue’ treatment and had assumed Octreotide (Sandostatin LAR) would be the drug of choice. However, my Oncologist prescribed Lanreotide (known in the UK as Somatuline Autogel and elsewhere as Somatuline Depot). Technically this is a hormone therapy (it’s not chemo).
Somatostatin Analogues (Octreotide/Lanreotide) are mainstay treatments for many Neuroendocrine Cancer patients and their introduction is a very significant factor in the improvement of both prognostic outcomes and quality of life. Both drugs are designed to control Carcinoid Syndrome (but can be used selectively in other NET syndromes) and both have anti-tumour effects. Check out my Lanreotide vs Octreotide comparison blog.
Although I didn’t relish the thought of any injection in the ‘rear end’ every 28 days for the rest of my life, I admit to being slightly relieved with his choice. I had been reading about patient experiences with the alternative, mainly the needle length and the occasional problems mixing the drug prior to injection. Although Lanreotide has a similar gauge (thickness), the needle is a good bit shorter and is deep subcutaneous rather than Octreotide LAR’s intramuscular (IM) route. No mixing is required as Lanreotide comes prefilled.
If you’re interested in the science, please be aware that a somatostatin analogue is a synthetic (manufactured) version of a naturally occurring hormone which inhibits the peptides and amines that can be dangerously hypersecreted by certain neuroendocrine tumours.
Following an Octreotide Scan, various areas lit up confirming the output from previous CT scans. It also confirmed new ‘hotspots’ for further investigation. This specialist scan confirmed I probably had working receptors to receive something known as a Somatostatin Analogue to help with combatting the effects of Carcinoid Syndrome (please note that not having working receptors does not mean there is no benefit of receiving somatostatin analogues). I was therefore prescribed daily Octreotide (self-injecting) whilst I was waiting for my first major ‘debulking’ surgery, This treatment did eventually lessen the main effect of the carcinoid syndrome, facial flushing. It wasn’t until after my first surgery that the facial flushing was dramatically reduced. I commenced Lanreotide on 9 Dec 2010 and I haven’t had a facial flush since. It’s worth adding that my Chromogranin A (CgA) blood test (correlated to tumour mass) did not return to normal until after a liver resection 3 months later. My 5HIAA urine test results (mainly correlated to serotonin levels) returned to normal prior to liver surgery in Apr 2011 indicating the Lanreotide was doing its job! Somatostatin Analogue side effects are to be expected and most people seem to have different and/or greater or lesser effects than others. The daily Octreotide did not bother me too much other than some discolouring of the stomach at the injection sites (i.e. black and blue!) ….I’m more observant nowadays, so it’s possible I may not have recorded this experience properly.
If you read the UK patient leafletwhich comes with each injection, you can see a list of potential side effects as long as your arm. Neuroendocrine Cancer comes with many signs, syndromes, symptoms and suspicions, so I always advise caution and some analysis when assigning reasons for problems encountered. For North America, the equivalent instructions can be found here (Somatuline Depot). I don’t know precisely why (……. I do have my suspicions), but I’m always very sceptical about the criteria used to compile the list of side effects for any medicine. In my own mind, I’m fairly certain that people have existing symptoms or new symptoms as a result of coincidental treatment that are erroneously labelled under drugs during trials.
You can also self-inject Lanreotide but I’m not ready for that yet! If you do self inject, please note it the site is “the upper outer part of your thigh”. Check out the Ipsen leaflet here.
I think the injection site is very important and getting this wrong will worsen the side effects. For the Healthcare Professional or trained family member administration, the site should be the superior external quadrant but not of the whole ‘butt’, it means of the left or right buttock that is being used on an alternative basis. If nurses think the whole ‘butt’, they might be tempted to stick it quite close to the ‘intergluteal cleft’ – not advisable!
Although the patient leaflets are very clear on how to administer the drug, once the location is established, I always discuss the following with the Nurse before I receive the ‘dart’:
1. The injection should have been removed from the fridge at least 30 minutes before treatment. However, please note Ipsen clarified in 2019 that the product can be put back in the fridge in the original packaging for later use, provided it has been stored for no longer than 24 hours at below 40 deg C (104 deg F) and the number of ‘temperature excursions’ does not exceed three. If you are taking the drug somewhere to be administered or were waiting on a home visit, this might help with scheduling issues.
2. Don’t pinch the skin, stretch it.
3. Put the needle in fast at 90 degrees, inject the drug slow – 20 seconds is recommended. As the drug is viscous, in any case, there is normally some resistance to a fast release.
4. Do not rub or massage the area after as this action can interfere with the formulation of the drug. This is clearly stated on the drug information leaflet, i.e. ” Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding. Do not rub or massage the injection site after administration”.
My experience with side effects. People have different experiences with side effects and just because a particular side effect is mentioned, does not mean to say that everyone will be troubled – many patients experience little or none. For me, over 7 years, I think I can attribute the following to Lanreotide:
itching but only on the legs below the knees centred on the ankles – and nearly always the right leg. Occasionally, the injection site will itch but only for a day or two. I have a tub of emollient cream (almond oil) on standby which seems to calm it down. Note …… a little bit of me thinks there could be a connection with vitamin/mineral deficiency and perhaps a coincidental occurrence and this problem seems much less of an issue over 7 years later. EDIT- could have been Hypothyroidism – click here.
minor pain at the injection site but this only lasts for an hour or two and I believe this to be associated with the administration of the injection, i.e. if the injection is done properly, I don’t really have this problem except for a second or two as it enters. Once, I had pain for 10 days. In my own experience, the best and least painful injections are those done by trained personnel who are confident.
small lumps form at the injection site which is alternating superior external quadrant of the each buttock. You may occasionally hear these being called ‘granulomas‘ or ‘injection site granulomas’. The issue of ‘injection site granulomas’ seems to figure in both Lanreotide and Octreotide. Gluteal injection site granulomas are a very common finding on CT and plain radiographs. They occur as a result of subcutaneous (i.e. intra-lipomatous) rather than intramuscular injection of drugs, which cause localised fat necrosis, scar formation and dystrophic calcification. But no-one seems to know why they occur with somatostatin analogues. I find that they are more conspicuous if the injection is done slightly too high which was my initial experience and they took months to fade. I opted to stand up for the first two injections and I attribute this decision for a slightly too high injection site. I now lie down which is actually recommended for the smaller and thinner patient. Although the lumps have reduced in size, I have not seen a new lump for some time indicating location might have been the cause. They sometimes show up on scans. This is not a new problem and has been highlighted for the last 10 years in academic papers. This particular paper is useful and the conclusion confirms this is not something that should worry patients too much. Read more here
fatigue normally within 24-48 hours of the injection but this is not consistent. Not even sure it can be classed as proper fatigue but it’s a ‘you need to sit down and fall asleep‘ feeling! When this occurs, it normally only lasts for 1 day before the normal energy levels return. Again, like the itching, this appears to be less of an issue today.
malabsorption. although the side effects of gastro-intestinal (GI) surgery and gallbladder removal can cause malabsorption issues leading to steatorrhea (basically the inability to digest fat properly); somatostatin analogues can cause or exacerbate existing steatorrhea, as they inhibit the production of digestive/pancreatic enzymes which aid fat digestion. Most months, I notice a marked but short-term increase in this problem normally within 48-72 hours of the injection.
elevated blood glucose. This is a new issue in 2018 but has been brewing for a year or two. The patient information leaflet for Lanreotide (and for Octreotide) clearly states that this is a potential side effect and also asks those who are already diabetic, to consult their doctor about monitoring doses of diabetic medicine. I’m working with my doctors to keep my blood glucose down to avoid becoming diabetic. Please read this article covering the connections between NETs and Diabetes
A few years ago, there was some ‘talk’ that somatostatin analogues were also able to stunt or reverse the growth of certain neuroendocrine tumours. Has this been the case for me? Possibly. I’ve had regular CT scans every 3-6 months and since two bouts of major surgery in 2010/2011, I’ve also had 3 x Octreoscans over the same period. I did once spend a day analysing 5 years of scan results looking for variations in size and concluded that there was a stable trend and potentially a fading of one or two of my largest liver tumours. I was reminded these two types of scans were not really precise enough to detect small millimetre increases or decreases and as there were other factors at play, there was little commitment to make this declaration. However, I did note in the summary of theCLARINETstudy, Lanreotide was associated with prolonged progression-free survival among patients with advanced, grade 1 or 2 (Ki-67 <10%) enteropancreatic, somatostatin receptor–positive neuroendocrine tumours with prior stable disease, irrespective of the hepatic tumour volume. In terms of its anti-proliferative effects, aninterim report from the CLARINET extension studysuggested longer-term Lanreotide treatment is well tolerated with ‘anti-tumour’ effects in patients with progressive disease. The final CLARINET open label extension studyreport additionally provided evidence for long-term PFS benefits of Lanreotide Autogel 120 mg in patients with indolent pancreatic and intestinal NETs.
There’s currently a trial ongoing in relation to Lanreotide and Lung NETs – read by clicking here.
I have my ups and downs and I do feel quite well most of the time. Most people tell me I look quite well too – lucky they can’t see my insides! Over the last 7 years, I’ve made some fairly significant adjustments to cope with my condition and maintain a reasonable quality of life – my monthly injection of Lanreotide is no doubt playing a big part.
Finally, please spend 5 minutes watching this fascinating video from Ipsen. It explains in easy terms how Lanreotide works. It also has a useful summary of the side effects at the end. Click here to watch the video.
I’ve just been enrolled onto a new service called HomeZone whereby the injection is now administered at my home via an Ipsen provided and funded nurse. Read here to see if you can also take advantage of this service.
In July 2018, I received my 100th injection of Somatuline Autogel (Lanreotide). I was very grateful to still be here so I thought it was worth a celebratory cake – injection themed!
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.
It was 10th November 2010 just after midnight. I gradually woke up after a marathon 9 hoursurgery – the first of what was to be several visits to an operating theatre. The last thing I remembered before going ‘under’ was the voices of the surgical staff. When I woke up, I remember it being dark and I appeared to be constrained and pinned down by the dozen or so tubes going in and out of my weak and battered body. I can still remember the feeling today, it was like I was pinned to the bed and I was completely vulnerable and helpless. However, what I mainly remember was my wife Chris holding my hand which gave me a great deal of much-needed comfort and security.
The build up to this day began on 26 July 2010 when I was given the news that I had metastaticNeuroendocrine Tumours and that the prognosis without any treatment wasn’t too good making the decision to have treatment a lot easier. I told my Oncologist to ‘crack on’ with whatever treatment would be required.
However, it wasn’t that easy and as I was yet to find out, Neuroendocrine Cancer isn’t a simple disease. I first had to undergo a plethora of other tests including specialist scans, blood and urine tests. The specialist scans (crucially) confirmed my tumours were ‘avid’ to a something called a ‘somatostatin analogue’. The scan also confirmed I had more tumours than initially thought. This was key to working out my treatment plan as I now had a grading, staging and I had the right tumour ‘receptors’ to assist along the way.
When I initially presented in May 2010, I hadn’t realised for some months that I was showing symptoms of one of the Neuroendocrine Tumour syndromes (in my case carcinoid syndrome‘. This was mainly facial flushing but thinking back, there was some diarrheaalbeit infrequent. The subsequent specialist blood and urine tests (CgA and 5HIAA respectively) were way out of range confirming both the diagnosis of tumour bulk and tumour activity respectively. The tumour activity (or function) is one thing which makes NETs different from most cancers and is caused by excessive secretion of specific hormonesapplicable to the primary location of the tumour. Thus why I had to be established on a ‘somatostatin analogue’ which is designed to inhibit the excessive secretion. I self-injected Octreotide daily for 2 months until the flushing was under control. When Neuroendocrine Tumours cause carcinoid syndrome, there is a risk of a phenomenon known as ‘Carcinoid Crisis’. This is the immediate onset of debilitating and life-threatening symptoms that can be triggered by a number of events including anaesthesia. As an additional precaution to prevent such complications, I was admitted on the 8th November 2010 in order to have an ‘Octreotide soak’ (Octreotide on a drip) prior to the surgery on 9th November 2010.
As is normal for such procedures, I had therisksexplained to me. There seemed to be a lot of risks on the list and my surgeon, Mr Neil Pearce, carefully explained each one. Death was on the list but I was happy to hear he had a 100% record on his ‘table’. Trust is an extremely important word when you’re in this situation.
As a snub to cancer, I refused the offer of a wheelchair and chose to walk to the operating theatre at around 2.30pm. So together with my ‘drip fed’ Octreotide trolley and wearing my surgical stockings and gown (carefully fastened at the rear!), I wandered down to the operating theatre with my escorting nurse.
The 9-hour operation was designed to debulk what was described as “extensive intra-abdominal neuroendocrine disease”. The operation comprised the removal of 3 feet of small intestine at the terminal ileum plus a right hemicolectomy, a mesenteric root dissection taking out the nodes on the superior mesenteric artery and a mesenteric vein reconstruction. With the assistance of a vascular surgeon, my NET surgeon also dissected out a dense fibrotic retro-peritoneal reaction which had encircled my aorta and cava below the level of the superior mesenteric artery. Phew! Thank goodness I was asleep 🙂
In those days, I had no idea that 10th November was NET Cancer Day. Some 8 years later I not only celebrate the fact that I woke up on this date after my first major surgery but that I have also woken up to the idea and inspiration behind NET Cancer Day in terms of an awareness window of opportunity.
However, on the basis that you can never have enough awareness windows, for me EVERY DAY IS NET CANCER DAY and via my own social media channels, I’m making sure everyone knows!
Thanks for listening
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Until I was diagnosed with metastatic Neuroendocrine Cancer, I didn’t have a clue about hormones – it’s one of those things you just take for granted. However, hormones are vital to human health (male and female) and it’s only when things go wrong you suddenly appreciate how important they are ……..like a lot of other things in life I suppose! The presence of over-secreting hormones (often called peptides throughout) is useful to aid diagnosis albeit it often means the tumours have metastasized. It’s also a frequent indication that the person has an associated NET syndrome.
This is a really complex area and to understand the hormone problems associated with Neuroendocrine Cancer, you need to have a basic knowledge of the endocrine and neuroendocrine systems. I’ve no intention of explaining that (!) – other than the following high level summary:
Glands in the endocrine system use the bloodstream to monitor the body’s internal environment and to communicate with each other through substances called hormones, which are released into the bloodstream. Endocrine glands include; Pituitary, Hypothalmus, Thymus, Pineal, Testes, Ovaries Thyroid, Adrenal, Parathyroid, Pancreas.
A Hormone is a chemical that is made by specialist cells, usually within an endocrine gland, and it is released into the bloodstream to send a message to another part of the body. It is often referred to as a ‘chemical messenger’. In the human body, hormones are used for two types of communication. The first is for communication between two endocrine glands, where one gland releases a hormone which stimulates another target gland to change the levels of hormones that it is releasing. The second is between an endocrine gland and a target organ, for example when the pancreas releases insulin which causes muscle and fat cells to take up glucose from the bloodstream. Hormones affect many physiological activities including growth, metabolism, appetite, puberty and fertility.
The Endocrine system. The complex interplay between the glands, hormones and other target organs is referred to as the endocrine system.
The Neuroendocrine System. The diffuse neuroendocrine system is made up of neuroendocrine cells scattered throughout the body. These cells receive neuronal input and, as a consequence of this input, release hormones to the blood. In this way they bring about an integration between the nervous system and the endocrine system (i.e. Neuroendocrine). A complex area but one example of what this means is the adrenal gland releasing adrenaline to the blood when the body prepares for the ‘fight or flight’ response in times of stress, ie, for vigorous and/or sudden action.
Hormones – the NET Effect
At least one or more hormones will be involved at various sites and even within certain syndromes, the dominant and offending hormone may differ between anatomical tumour sites. For example, NETs of the small intestine may overproduce serotonin and other hormones which can cause a characteristic collection of symptoms currently called carcinoid syndrome. The key symptoms are flushing,diarrhea and general abdominal pain, loss of appetite, fast heart rate and shortness of breath and wheezing. The main symptom for me was facial flushing and this was instrumental in my eventual diagnosis. The fact that I was syndromic at the point of diagnosis made it easier to discover, albeit the trigger for the investigation was a fairly innocuous event. Other types of NETs are also affected by the overproduction of hormones including Insulinomas, Gastrinomas, Glucagonomas, VIPomas, Somatostatinomas, and others. These can cause their own syndromes and are not part of carcinoid syndrome as some organisations incorrectly state. For more on NET syndromes – Read Here.
So are hormones horrible?
Absolutely not, they are essential to the normal function of the human body. For example if you didn’t have any of the hormone Serotonin in your system, you would become extremely ill. On the other hand, if your glands start secreting too much of certain hormones, your body could become dysfunctional and in some scenarios, this situation could become life threatening. So hormones are good as long as the balance is correct. NET patients with an oversecreting tumor may be classed as “functional”.
Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows. Many NET patients are deemed to be “non-functioning” with normal hormone levels. It’s also accurate to say that many can move from one stage to the other.
Location Location Location
It’s accurate to say that the type and amount of hormone secretion differs between locations or sites of the functional tumor and this can also create different effects. The division of NETs into larger anatomical regions appears to differ depending on where you look but they all look something likes this:
Foregut NETs: In the respiratory tract, thymus, stomach, duodenum, and pancreas. This group mostly lack the enzyme aromatic amino decarboxylase that converts 5-HTP (5-Hydroxytryptophan – a precursor to serotonin) to serotonin (5-HT); such tumours tend to produce 5-HTP and histamine instead of serotonin.
The Pancreas is a particularly prominent endocrine organ and can produce a number of different syndromes each with their associated hormone oversecretion – although many can be non-functional (at least to begin with), (see below for more detail). It’s also possible to see predominantly serotonin secreting tumors in places such as the pancreas (although what you would call that type of NET is open for debate).
Lung NETs rarely produce serotonin, but may instead secrete histamine causing an ‘atypical’ carcinoid syndrome with generalized flushing, diarrhea, periorbital oedema, lacrimation and asthma. They may also produce adrenocorticotropic hormone (ATCH) or corticotropin-releasing factor (CRP), resulting in an ectopic Cushing’s syndrome. Please note the respiratory tract and thymus are not really anatomically pure ‘Foregut’ – but in NETs, grouped there for convenience.
Gastric (Stomach) NETs. Gastrin is the main hormone but there can also be histamine producing an atypical carcinoid syndrome effect.
Midgut NETs: In the small intestine, appendix, and ascending colon. For example, serotonin secreting tumors tend to be associated with carcinoid syndrome which tends to be associated with midgut NETs and this is normally the case. Many texts will also tell you that a syndrome only occurs at a metastatic stage. Both are a good rule of thumb but both are technically incorrect. For example, ovarian NETs can have a form of carcinoid syndrome without liver metastasis (tends to be described as atypical carcinoid syndrome).
Hindgut NETs (transverse, descending colon and rectum) cannot convert tryptophan to serotonin and other metabolites and therefore rarely cause carcinoid syndrome even if they metastasise to the liver.
Less Common Locations – there are quite a few less common NET locations which may involve less common hormones – some are covered below including the key glands contributing to NETs.
Unknown Primary? – One clue to finding the primary might be by isolating an offending hormone causing symptoms.
The key NET hormones
I used the example of Serotoninabove because it is the most cited problem with NET Cancer although it does tend to be most prevalent in midgut tumors. Serotonin is a monoamine neurotransmitter synthesized from Tryptophan, one of the eight essential amino acids (defined as those that cannot be made in the body and therefore must be obtained from food or supplements). About 90% of serotonin produced in the body is found in the enterochromaffin cells of the gastrointestinal (GI) tract where it is used mainly to regulate intestinal movements amongst other functions. The remainder is synthesized in the central nervous system where it mainly regulates mood, appetite, and sleep. Please note there is no transfer of serotonin across the blood-brain barrier.
Alterations in tryptophan metabolism may account for many symptoms that accompany carcinoid syndrome. Serotonin in particular is the most likely cause of many features of carcinoid syndrome as it stimulates intestinal motility and secretion and inhibits intestinal absorption. Serotonin may also stimulate fibroblast growth and fibrogenesis and may thus account for peritoneal and valvular fibrosis encountered in such tumours; serotonin, however, it is said not to be associated with flushing. The diversion of tryptophan to serotonin may lead to tryptophan deficiency as it becomes unavailable for nicotinic acid synthesis, and is associated with reduced protein synthesis and hypoalbuminaemia; this may lead to the development of pellagra (skin rash, glossitis, stomatitis, confusion/dementia).
Serotonin is also thought to be responsible for ‘right sided’ heart disease (Carcinoid Heart Disease). It is thought that high levels of serotonin in the blood stream damages the heart, leading to lesions which cause fibrosis, particularly of the heart valves. This generally affects the right side of the heart when liver metastases are present. The left side of the heart is usually not affected because the lungs can break down serotonin. Right sided heart failure symptoms include swelling (edema) in the extremities and enlargement of the heart.
Whilst serotonin can be measured directly in the blood, it’s said to be more accurate to measure 5HIAA (the output of serotonin) via blood or urine, the latter is said to be the most accurate.
Tackykinins include Substance P, Neurokinin A, Neuropeptide K and others. They are active in the enterochromaffin cells of the GI tract but can also be found in lung, appendiceal and ovarian NETs, and also in Medullary Thyroid Carcinoma and Pheochromocytomas. They are thought to be involved in flushing and diarrhea in midgut NETs. The most common tachykinin is Substance P, which is a potent vasodilator (substances which open up blood vessels). Telangiectasias are collections of tiny blood vessels which can develop superficially on the faces of people who have had NETs for several years. They are most commonly found on the nose or upper lip and are purplish in color. They are thought to be due to chronic vasodilatation.
Histamine is a hormone that is chemically similar to the hormones serotonin, epinephrine, and norepinephrine. After being made, the hormone is stored in a number of cells (e.g., mast cells, basophils, enterochromaffin cells). Normally, there is a low level of histamine circulating in the body. However (and as we all know!), the release of histamine can be triggered by an event such as an insect bite. Histamine causes the inconvenient redness, swelling and itching associated with the bite. For those with severe allergies, the sudden and more generalized release of histamine can be fatal (e.g., anaphylactic shock). Mast cell histamine has an important role in the reaction of the immune system to the presence of a compound to which the body has developed an allergy. When released from mast cells in a reaction to a material to which the immune system is allergic, the hormone causes blood vessels to increase in diameter (e.g., vasodilation) and to become more permeable to the passage of fluid across the vessel wall. These effects are apparent as a runny nose, sneezing, and watery eyes. Other symptoms can include itching, burning and swelling in the skin, headaches, plugged sinuses, stomach cramps, and diarrhea. Histamine can also be released into the lungs, where it causes the air passages to become constricted rather than dilated. This response occurs in an attempt to keep the offending allergenic particles from being inhaled. Unfortunately, this also makes breathing difficult. An example of such an effect of histamine occurs in asthma. Histamine has also been shown to function as a neurotransmitter (a chemical that facilitates the transmission of impulses from one neural cell to an adjacent neural cell).
In cases of an extreme allergic reaction, adrenaline is administered to eliminate histamine from the body. For minor allergic reactions, symptoms can sometimes be lessened by the use of antihistamines that block the binding of histamine to a receptor molecule. Histamine is thought to be involved with certain types and locations of NET, including Lung and foregut NETs where they can cause pulmonary obstruction, atypical flush and hormone syndromes.
Histamine, another amine produced by certain NETs (particularly foregut), may be associated with an atypical flushing and pruritus; increased histamine production may account for the increased frequency of duodenal ulcers observed in these tumours.
Kallikrein is a potent vasodilator and may account for the flushing and increased intestinal mobility.
Although prostaglandins are overproduced in midgut tumours, their role in the development of the symptoms of carcinoid syndrome is not well established but triggering peristalsis is mentioned in some texts.
Bradykinin acts as a blood vessel dilator. Dilation of blood vessels can lead to a rapid heartbeat (tachycardia) and a drop in blood pressure (hypotension). Dilation of blood vessels may also be partly responsible for the flushing associated with carcinoid syndrome.
Gastrin is a hormone that is produced by ‘G’ cells in the lining of the stomach and upper small intestine. During a meal, gastrin stimulates the stomach to release gastric acid. This allows the stomach to break down proteins swallowed as food and absorb certain vitamins. It also acts as a disinfectant and kills most of the bacteria that enter the stomach with food, minimising the risk of infection within the gut. Gastrin also stimulates growth of the stomach lining and increases the muscle contractions of the gut to aid digestion. Excess gastrin could indicate a NET known as a Gastric NET (stomach) or a pNET known as Gastrinoma (see pancreatic hormones below).
Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland. Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone. This means that it acts to reduce calcium levels in the blood. This hormone tends to involve Medullary Thyroid Carcinoma and Hyperparathyroidism in connection to those with Multiple Endocrine Neoplasia. Worth also pointing out the existence of Calcitonin Gene-Related Peptide (CGRP) which is a member of the calcitonin family of peptides and a potent vasodilator. Please note that hypothyroidism is often a side effect of NETs or treatment for NETs – please click here to read about the connection.
HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands. However, I’m only covering the pituitary and adrenal due to their strong connection with NETs.
Adrenocorticotropic hormone (ATCH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ATCH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ATCH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ATCH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ATCH may be due to:
Cushing’s disease – this is the most common cause of increased ATCH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ATCH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.
A tumour outside the pituitary gland, producing ATCH is known as an ectopic ATCH. With NETs, this is normally a pNET, Lung/Bronchial/Pulmonary NET or Pheochromocytoma.
Adrenaline and Noradrenline
These are two separate but related hormones and neurotransmitters, known as the ‘Catecholamines’. They are produced in the medulla of the adrenal glands and in some neurons of the central nervous system. They are released into the bloodstream and serve as chemical mediators, and also convey the nerve impulses to various organs. Adrenaline has many different actions depending on the type of cells it is acting upon. However, the overall effect of adrenaline is to prepare the body for the ‘fight or flight’ response in times of stress, i.e. for vigorous and/or sudden action. Key actions of adrenaline include increasing the heart rate, increasing blood pressure, expanding the air passages of the lungs, enlarging the pupil in the eye, redistributing blood to the muscles and altering the body’s metabolism, so as to maximise blood glucose levels (primarily for the brain). A closely related hormone, noradrenaline, is released mainly from the nerve endings of the sympathetic nervous system (as well as in relatively small amounts from the adrenal medulla). There is a continuous low-level of activity of the sympathetic nervous system resulting in release of noradrenaline into the circulation, but adrenaline release is only increased at times of acute stress. These hormones are normally related to adrenal and extra adrenal NETs such as Pheochromocytoma and Paraganglioma. Like serotonin secreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured (amongst other tests) by 24 hour urine test very similar to 5HIAA (with its own diet and drug restrictions). It’s known as 24-hour urinary catacholamines and metanephrines. Worth noting that adrenaline is also known as Epinephrine (one of the 5 E’s of Carcinoid Syndrome).
This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome. Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.
Other hormones related to ACC include:
Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.
Estrogen – early signs of puberty in children, enlarged breast tissue in males.
Aldosterone – weight gain, high blood pressure.
Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.
Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low. A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1
Pancreatic Hormones (Syndromes)
Pancreatic neuroendocrine tumors form in hormone-making cells of the pancreas. You may see these described as ‘Islet Cells’ or ‘Islets of Langerhans’ after the scientist who discovered them. Pancreatic NETs may also be functional or non-functional:
Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows.
There are different kinds of functional pancreatic NETs. Pancreatic NETs make different kinds of hormones such as gastrin, insulin, and glucagon. Functional pancreatic NETs include the following:
Gastrinoma: A tumor that forms in cells that make gastrin. 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. When increased stomach acid, stomach ulcers, and diarrhea are caused by a tumor that makes gastrin, it is called Zollinger-Ellison syndrome. A gastrinoma usually forms in the head of the pancreas and sometimes forms in the small intestine. Most gastrinomas are malignant (cancer).
Insulinoma: A tumor that forms in 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. An insulinoma forms in the head, body, or tail of the pancreas. Insulinomas are usually benign (not cancer).
Glucagonoma: A tumor that forms in cells that 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). A glucagonoma usually forms in the tail of the pancreas. Most glucagonomas are malignant (cancer).
Pancreatic Polypeptide (PPoma). A pancreatic polypeptide is a polypeptide hormone secreted by the pancreatic polypeptide (PP) cells of the islets of Langerhans in the endocrine portion of the pancreas. Its release is triggered in humans by protein-rich meals, fasting, exercise, and acute hypoglycemia and is inhibited by somatostatin and intravenous glucose. The exact biological role of pancreatic polypeptide remains uncertain. Excess PP could indicate a pNET known as PPoma.
Other types of tumors: There are other rare types of functional pancreatic NETs that make hormones, including hormones that control the balance of sugar, salt, and water in the body. These tumors include:
VIPomas, which make vasoactive intestinal peptide. VIPoma may also be called Verner-Morrison syndrome, pancreatic cholera syndrome, or the WDHA syndrome (Watery Diarrhea, Hypokalemia (low potassium)and Achlorhydria).
Somatostatinomas, which make somatostatin. Somatostatin is a hormone produced by many tissues in the body, principally in the nervous and digestive systems. It regulates a wide variety of physiological functions and inhibits the secretion of other hormones, the activity of the gastrointestinal tract and the rapid reproduction of normal and tumour cells. Somatostatin may also act as a neurotransmitter in the nervous system.
Having certain syndromes can increase the risk of pancreatic NETs.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Multiple endocrine neoplasia type 1 (MEN1) syndrome is a risk factor for pancreatic NETs.
Signs and symptoms of pancreatic NETs
Signs or symptoms can be caused by the growth of the tumor and/or by hormones the tumor makes or by other conditions. Some tumors may not cause signs or symptoms. Check with your doctor if you have any of these problems.
Signs and symptoms of a non-functional pancreatic NET
A non-functional pancreatic NET may grow for a long time without causing signs or symptoms. It may grow large or spread to other parts of the body before it causes signs or symptoms, such as:
A lump in the abdomen.
Pain in the abdomen or back.
Yellowing of the skin and whites of the eyes.
Signs and symptoms of a functional pancreatic NET
The signs and symptoms of a functional pancreatic NET depend on the type of hormone being made.
Too much gastrin may cause:
Stomach ulcers that keep coming back.
Pain in the abdomen, which may spread to the back. The pain may come and go and it may go away after taking an antacid.
The flow of stomach contents back into the esophagus (gastroesophageal reflux).
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.
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.
Weight loss for no known reason.
Sore tongue or sores at the corners of the mouth.
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.
Weight loss for no known reason.
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.
Steatorrhea (very foul-smelling stool that floats).
Yellowing of the skin and whites of the eyes.
Weight loss for no known reason.
Too much pancreatic polypeptide may cause:
an enlarged liver.
Clearly the presenting symptoms will give doctors a clue to the oversecreting hormone (see list above). Excessive secretions or high levels of hormones and other substances can be measured in a number of ways. For example:
Well known tests for the most common types of NET include 5-Hydroxyindoleacetic Acid (5-HIAA) 24 hour urine test which is also measured by a blood draw. Note: -tumor markers can be measured simultaneously e.g. Chromogranin A (CgA) blood test and/or Pancreastatin as there can very often be a correlation between tumour mass and tumour secreting activity. CgA / Pancreastatin is a blood test which measures a protein found in many NET tumour cells. These marker tests are normally associated with tumour mass rather than tumour functionality.
By measuring the level of 5-HIAA in the urine or blood, healthcare providers can calculate the amount of serotonin in the body (5-HIAA is a by-product of serotonin). 5-HIAA test is the most common biochemical test for carcinoid syndrome or the degree of how ‘functional’ tumours are. If you’ve understood the text above, you can now see why there are dietary and drug restrictions in place prior to the test.
Pancreatic Hormone testing. There are other tests for other hormones and there is a common test which measured the main hormones seen in NETs. It may be called different things in different countries, but in UK, it’s known as a ‘Fasting Gut Hormone Profile‘.
Scratching the surface here so for a comprehensive list of marker tests for NETs, have aread here.
Treatment for Over-secreting Hormones
Of course, reducing tumour bulk through surgery and other treatment modalities, should technically reduce over-secretion (I suspect that doesn’t work for all). Other treatments may have the dual effect of reducing tumour burden and the effects of hormone oversecretions.
One of the key treatment breakthroughs for many NET cancer patients, is the use of ‘Somatostatin Analogues’ mainly branded as Octreotide (Sandostatin) or Lanreotide (Somatuline). People tend to associate these drugs with serotonin related secretions and tumours but they are in actual fact useful for many others including the pancreatic NETs listed above. Patients will normally be prescribed these drugs if they are displaying these symptoms but some people may be more avid to the drug than others and this may influence future use and dosages. This is another complex area but I’ll try to describe the importance here in basic terms. Somatostatin is a naturally occurring protein in the human body. It is an inhibitor of various hormones secreted from the endocrine system (some of which were listed above) and it binds with high affinity to the five somatostatin receptors found on secretory endocrine cells. NETs have membranes covered with receptors for somatostatin. However, the naturally occurring Somatostatin has limited clinical use due to its short half-life (<3 min). Therefore, specific somatostatin analogues (synthetic versions) have been developed that bind to tumours and block hormone release. Thus why Octreotide and Lanreotide do a good job of slowing down hormone production, including many of the gut hormones controlling emptying of the stomach and bowel. It also slows down the release of hormones made by the pancreas, including insulin and digestive enzymes – so there can be side effects including fat malabsorption.
The recent introduction of Telotristat Ethyl(XERMELO) is interesting as that inhibits a precursor to serotonin and reduces diarrhea in those patients where it is not adequately controlled by somatostatin analogues.
Other than the effects of curative or cytoreductive surgery, some NETs may have very specialist drugs for inhibiting the less common hormone types. This is not an exhaustive list.
Worth also noting that oversecreting hormones can contribute to a phenomenon (currently) known as Carcinoid Crisis – read more here. For catacholamine secreting tumors (Pheochromocytoma/Paraganglioma), this may be known as Intraoperative Hypertensive Crisis
Sorry about the long article – it’s complex and you should always consult your specialist about issues involving hormones, testing for hormones and treating any low or high scores.