5 years ago today, I had a bunch of lymph nodes removed. Two separate areas were resected, only one was showing growth but both were showing up as hotspots on an Octreoscan. I had known since shortly after diagnosis in 2010 that ‘hotspots’ were showing in my left ‘axillary’ lymph nodes (armpit) and my left ‘supraclavicular fossa’ (SCF) lymph nodes (clavicle area). Some 10 months previously, I had a major liver resectionand 5 months prior to the liver resection, I had a small intestinal primary removedincluding work on some associated complications. There had always been a plan to optimise cytoreduction of my distant metastases, it was just a matter of timing. I still can’t get my head round why metastases from a small intestinal NET managed to get to this area but not others!
Distant nodal metastasis treatment
A total of 9 nodes were removed from my left armpit (a very common operation for breast cancer patients). The surgeon had inspected the area and found some were palpable and my normally stable Chromogranin Amarker was showing a small spike out of range. During the same operation under general anaesthetic, an ultrasound directed SCF nodal ‘exploration’ was carried out. When biopsied, 5 of the 9 resected axillary nodes were tested positive (Ki-67 <5) but the 5 SCF nodes removed were tested negative. The subsequent Octreoscan still lit up in the left SCF area but the lights on the left axillary area were ‘extinguished’. There is no pathological enlargement or pain in the left SCF area – so this is just monitored.
Apart from a very faint scar in the left SCF area, there does not appear to be any side effects from this exploratory surgery. The left axillary area cut is well hidden by hair growth but I do sense a lack of feeling in the area. Additionally, I have a very mild case of lymphedema in my left hand which occasionally looks slightly swollen – the consequences of cancerand its treatment. Fluid build-up, or post-operative seroma, can be a side effect of a lymphadenectomy. In fact, within a month of the operation, I had to have circa 160mls of fluid removed on 4 occasions from my armpit. It was uncomfortable and painful, resulting in additional time off work. The surgeon used a fine needle aspiration to draw out the fluid, a painless procedure. It eventually cleared up and everything was back to normal. The specialist said my left arm would be slightly more susceptible to infections and suggested to avoid using my left arm for blood draws and other invasive procedures and injuries.
Other close calls (“to cut or not to cut”)
I have a 19mm thyroid lesion which was pointed out to me in 2013. This has been biopsied with inconclusive results. Although the thyroid is an endocrine gland, it looks like a non-NET problem so far. Thyroid nodules are in fact very common and statistically, 50-70% of all 50-70 year olds will have at least one nodule present (i.e. if you are in your 50s, there is a 50% chance you will have one nodule and so on). The vast majority will never bother a person while they live. I attend an annual Endocrine MDT where this is monitored in close coordination with the NET MDT. It’s actually managed by the same surgeon who carried out the nodal work above.
I have a 3mm lung nodule, discovered in 2011. Apparently, lung nodules are a pretty common incidental finding with 1 per 500 X-rays and 1 per 100 CT scans finding them. This is monitored and hasn’t changed since noted.
A fairly common disposition of metastatic Neuroendocrine Tumours (NETs) is a primary with associated local/regional secondary’s (e.g. lymph nodes, mesentery and others) with liver metastases. Technically speaking, the liver is distant. However, many metastatic patients have additional and odd appearances in even more distant places, including (but not limited to) the extremities and the head & neck. In certain NETs, these might be an additional primary (e.g. in the case of Multiple Endocrine Neoplasia (MEN); or they could even be a totally different cancer. The worry with NETs is that the ‘little suckers‘ can sometimes make these surprise appearances given that neuroendocrine cells are everywhere.
Cancer doesn’t just spread through the blood steam, it can also spread through the lymphatic system. This is a system of thin tubes (vessels) and lymph nodes that run throughout the body in the same way blood vessels do. The lymph system is an important part of our immune system as it plays a role in fighting bacteria and other infections; and destroying old or abnormal cells, such as cancer cells. The lymphatic system also contains organs, some of which feature regularly in NETs. If cancer cells go into the small lymph vessels close to the primary tumour they can be carried into nearby lymph glands where they stick around. In the lymph glands they may be destroyed (that is actually one of the jobs of the lymph glands) but some may survive and grow to form tumours in one or more lymph nodes.
I also had the usual bulky chains of lymph node metastases in or around the mesentery that frequently appear with an abdominal primary (in my case the small intestine). These were all removed as part of my primary resection. However, I knew since shortly after diagnosis in 2010 that I had ‘hotspots’ in my left ‘axillary’ lymph nodes (armpit) and my left ‘supraclavicular fossa’ (SCF) lymph nodes (clavicle). These were found on Octreoscan but at the time, they were not pathologically enlarged – just ‘lighting up’. They also light up on Ga68 PET.
In early 2012, 15 months after removal of primary and 10 months after liver resection, one of the axillary lymph nodes became palpable (signs of growth) and this coincided with a small spike in Chromogranin A. A total of 9 nodes were removed very shortly after this surveillance, 5 of which tested positive for NETs (Ki-67 <5%). As part of the same operation, 5 SCF left clavicle nodes were removed but tested negative. On a subsequent Octreoscan, the armpit was clear but the clavicle area still lit up. However, there is no pathological enlargement or pain – so this is just monitored. Also lights up on Ga68 PET I have a 3mm lung ‘nodule’, discovered in 2011. Apparently, lung nodules are a pretty common incidental finding with 1 per 500 X-rays and 1 per 100 CT scans finding them. This is monitored.
I have a 19mm thyroid ‘lesion’ which was pointed out to me in 2013. This has been biopsied with inconclusive results. Although the thyroid is an endocrine gland, it looks like a non-NET problem to date. Thyroid nodules are in fact very common and statistically, 50-70% of all 50-70 year olds will have at least one ‘nodule’ present (i.e. if you are in your 50s, there is a 50% chance you will have one nodule and so on). The vast majority will never bother a person while they live. That said, my thyroid blood tests are abnormal and on 20th March 2018, following an Endocrine appointment, I was put on a trial dose of 50mcg of Levothyroxine to counter the thyroid panel results indicating hypothyroidism. Levothyroxine is a thyroid hormone replacement. Early in 2017, during my Endocrine MDT, a surveillance ultrasound spotted a slightly enlarged lymph node on the right side (measuring 9mm x 9mm) described as a ‘level 4’ node (a location indicator meaning the ‘lower jugular group’). The report was passed to the NET MDT for their consideration with the surgical rep on the Endocrine MDT recommending a conservative approach – the NET MDT agreed. I suspect that’s right, it’s still below the worry threshold, nothing is palpable (no lumps) and I don’t have any specific symptoms. There could have been a number of reasons for the enlargement and it might even be back to normal size on my next scan (spoiler alert – it was). All my issues have been left-sided to date, so that was interesting. That said, I did have an MRI in 2014 to investigate pain and a swelling at the site of my right ‘sternoclavicular’ joint – subsequently declared a non-issue. Showed as inflammation on recent Ga68 PET.
Life as a metastatic Neuroendocrine Cancer patient is interesting and efficient surveillance is absolutely critical.
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.
When I was diagnosed with metastatic Neuroendocrine Cancer on 26 July 2010, I just wanted them to hurry up and fix my body so I could get back to normal. My expectations of speed turned out to be wildly inaccurate and in hindsight, I was also wildly naive. You see, with Neuroendocrine Cancer, particularly well-differentiated, low or medium grade tumours, it sometimes doesn’t work as fast as you would think and there are good reasons for that.
The complexity of the condition needs some consideration as the physicians work up a treatment plan. I’m quite happy and content they took their time, rather than rush into the wrong decisions. If you think about it, this is an advantage with low and medium grade NETs……you normally have some time to get the ducks in a line (and there are some pretty important ducks in that line).
Here’s a very short video discussing this during a patient video shoot: Click here.
I had a confirmed biopsy result following some incidental CT scans and other tests. However, they now needed further checks and marker tests to work out the extent of the disease. So the timeline leading up to major surgery ended up like this:
Diagnosis: 26 July 2010. Met with Oncologist. Grade 2 Small Intestine NET with distant metastasis (Stage 4)
Chromogranin A and 5HIAA: submitted 28 July. Results received 13 August – both elevated, indicating and confirming tumour bulk and function status respectively
Octreotide Scan:17-19 August. Report issued 24 August – confirmed CT plus additional distant hotshots. Also confirmed my tumour receptors were avid to somatostatin analogues.
Daily Octreotide Injections: Started 9 September to control syndrome (derisk surgery)
Referred to NET Multi-Disciplinary Team (MDT): 15 September – they now had sufficient data to form a treatment plan.
Holiday: Late September (it was booked and I felt OK, why not!)
Further MDT assessment and consultations: 1- 7 October
Bland Liver Embolisation: 19 October
First Surgery: 9 November – to remove primary and debulk local and regional spread.
You can read the rest of my treatment background here.
So it took 75 days from diagnosis to opening me up to remove the first batch of tumours. With reasonably slow-growing tumours, that isn’t really a long time when you consider they had probably been growing inside me for several years. I’m sure others waited even longer.
Sometimes rushing straight into the operating theatre isn’t really the best option. I’m still here!
One of the most discussed and sometimes confusing subjects on forums is the staging and grading of Neuroendocrine Neoplasms (NENs). Mixing them up is a common error and so it’s important to understand the difference despite the apparent complexity. If I was to make a list of questions for my specialist/Oncologist at diagnosis, it would include “What is the stage, grade and differentiation of my cancer”. To enable me to synchronise with the documented guidance, I’m going to use the following WHO 2017 approved terms in this post:
Neuroendocrine Neoplasm (NEN) – all types of Neuroendocrine tumour of whatever grade (please note Neoplasm is another word for tumour)
Neuroendocrine Tumour (NET) – all well-differentiated tumours (an explanation of differentiation will be provided below)
Neuroendocrine Carcinoma (NEC) – all poorly differentiated tumours
Stage vs Grade
In the most basic of terms, stage is the spread or extent of cancer and grade is the aggressiveness of cancer. They are totally different things and an understanding of both is important as they are critical to predict outcome (to a certain extent) and guide therapy. There is no correlation between the two, you can have the lowest grade with the highest stage (actually very common with NETs).
As patients, we deal with many medical specialists during diagnosis and subsequent treatment. However, we rarely meet the pathologist who plays a critical role in the outcome. Precise diagnosis is what drives patient decisions and treatment. If the pathology is wrong, everything that follows could be incorrect as well. It’s a very important area.
Why is differentiation important?
To fully understand grading, you also need to understand the concept of ‘differentiation’. In the most basic of terms, ‘differentiation’ refers to the extent to which the cancerous cells resemble their non-cancerous counterparts. This is an important point for NETs because many low-grade tumour cells can look very similar to normal cells. The differentiation of a NET has an impact on both prognostics and treatment regimes.
NENs fall into one of three grades based on their differentiation and their proliferative rate. The proliferative rate is measured mainly using two methods known as Miotic Count and Ki-67 index, the latter seems to be more frequently used (but see below for Lung NETs). The Ki-67 index can usually be determined, even in cases of small biopsies but Mitotic rate counting requires a moderate amount of tumour tissue (at least 50 HPFs or 10 mm) and may not be feasible for small biopsies. The Miotic Count method may be preferred or used in addition to Ki-67 for certain Lung NET scenarios as it is said to be more helpful in distinguishing atypical from typical NET (what some might ‘old fashionably’ and incorrectly refer to as Lung Carcinoid tumours), and for small and large cell lung Neuroendocrine Carcinomas (NEC).
Some of you may have heard the term ‘moderately differentiated’ which tended to align with an intermediate grade or Grade 2. However, please note that the term moderately differentiated as a classification was phased out in 2010 by WHO reducing from 3 differentiation levels to 2. Grade 2 is also defined as well differentiated but based on different proliferative rate (see table). High grade was normally referred to as Neuroendocrine Carcinoma indicating it is a faster growing and more aggressive cancer. However, see below for an important change to high grade classification.
Grading – Key WHO 2017 Changes
WHO Classifications of Cancer are published in something known in medical world as “The Blue Book”. For NETs, the 2017 version comprises only the “WHO Classification of Tumours of Endocrine Organs”. Technically this would preclude the digestive system and lung NETs but I’m told on good authority from world leading pathologists and from listening to lectures at ENETS 2018, that the classification in the leading picture is to be used for all NENs. Worth also noting that the latest ENETS Guidelines are already using the new grading terms. Many sites remain out of date so be careful where you look.
The 2017 World Health Organisation (WHO) classification sub-divided Grade 3 into two new entities: a well differentiated high-grade NET and a poorly differentiated high-grade NEC. There may also be a cut-off point in proliferative rate (i.e. Ki-67) between NET and NEC in relation to potential treatment strategies (55% is mentioned for pNETs but I’m currently investigating).
The Grade 1 to 2 Ki-67 cut-off is changed from 2 to < 3 for clarification purposes. There was some discussion as to whether it should be <5 but this was not accepted.
Well differentiated High Grade NETs are now recognised. These are known as a NET rather than a NEC. Both Grade 3 (NET) and Grade 3 (NEC) have the same biopsy marker cut-offs as per the leading slide but it is thought that a threshold reading of 55% could have some influence on the treatment regime. For example, a well differentiated tumour with a Ki67 of less than 55% might benefit from the same treatment given to Grade 1 or 2 patients, whereas a well differentiated tumour with a Ki67 of more than 55% might benefit from the same treatment given to poorly differentiated NEC. Only a guideline and I suspect this is like many things in NENs, very individual, relies on many factors, so your specialist will drive this accordingly. You may see these 2 grades listed as Grade 3a for NET and Grade 3b for NEC.
Previously, Pheochromocytoma did not have an official grading regime, i.e. they were just benign or malignant. Now they are using the same grading system as above. I’m assuming this is the same for Paraganglioma and I will confirm in due course. This is an excellent change and a continuation from the WHO 2010 classification where there was great emphasis away from a benign/malignant classification to formal grade levels on the basis that all NETs have malignant potential.
It also introduced a change to the naming of mixed cell tumours from Mixed AdenoNeuroendocrine Carcinoma (MANEC) to Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN). A full explanation of this MiNEN will follow but I would suggest the use of the term ‘Neoplasm’ has been chosen rather than ‘Carcinoma’ is because these neoplasms can be well or poorly differentiated.
It’s not possible at this time to acquire copies of the official output but I will keep this blog live.
The source material for the 2017 version of this article.
From leading Pathologist Dr Anthony Gill – Remember this is based on Endocrine Organs only but it will eventually apply to all. I am awaiting access to free documentation to update this article further – only ones I can currently find are not free!
Misc Grading Issues
The proliferative rate can be diverse in NENs, so sampling issues can limit the accuracy of grading. More substantial samples of tumour are therefore preferable for grading thus why the Ki-67 index is preferred for biopsies where large amounts of tissue may not be available. The distinction of low-grade from intermediate grade can be challenging when using small samples. A couple of interesting observations about NET grading which I spotted during my research and ‘forum watching’. You can have multiple primary tumours and these might have different Ki-67 scores. Additionally, on larger tumours, Ki-67 scores can be different on different parts of the tumour. And something I know from my own experience, secondary tumours can have different Ki-67 scores than primary – even a different grade. In my own case, my liver secondary tumours were graded higher than my primary which according to my surgeon is in keeping with a clone of the disease having become more aggressive over time. Royal Free Hospital NET Centre indicates a person’s grade should be taken from the highest biopsy grade taken. This is a fairly complex area but a recent study published by the US National Institute of Health and many anecdotal comments made by NET specialists indicates that is a fairly common scenario.
Staging is the extent or spread of disease. Most types of cancer have 4 stages, numbered from 1 to 4 indicating a rising spread as the number is bigger. Often doctors write the stage down in Roman numerals, perhaps this is to stop any confusion between standard numbers used for Grades? So you may see stages written as I, II, III and IV. In addition to this standard method, there is also an agreed model known as TNM (Primary Tumour, Regional Node, Distant Metastasis) which is essentially a more detailed staging definition when combined with the Stage 1-4 model. Please note with TNM models, there could be different stage descriptions depending on the location of the primary tumour and similarly different TNM models for different tumour locations.
WHO 2017 changes
WHO 2017 has recommended enhancements to the TNM system mainly the use of additional suffixes indicating the extent of lymph node involvement. Details to follow when I can free access.
The following example shows the stage descriptions for a NET of the small intestine (the others are similar but worded accordingly for that part of the anatomy):
Stage I tumour is less than 1 cm in size and has not spread to the lymph nodes or other parts of the body.
Stage II tumour is greater than 1 cm in size and has started to spread beyond the original location, but has not spread to the lymph nodes or other parts of the body.
Stage III is any size tumour that has spread to nearby areas of the body and also to at least one lymph node.
Stage IV is any size tumour that has spread to one or more lymph nodes and has also spread to other, more distant areas of the body (such as the liver).
It’s also worth pointing out that Stage IV does not necessarily mean a cancer is more dangerous than other cancers of lesser stages. This is an important point for NETs where Stage 4 can be matched up with a low-grade tumour i.e. Stage 4 for lower grade NETs is very often not the ‘red flag’ it is for other more aggressive cancers. For example, doctors may surgically remove a Stage IV NET, while surgery might not help a patient with a cancer of a higher grade at such a late stage.
Sometimes doctors use the letters to further divide the number categories – for example, stage 2A or stage 3B. This is normally to clarify or provide more detail of the primary tumour size/invasion in conjunction with the TNM model.
You may also see something called Stage 0 which is for ‘Carcinoma in situ’. It means that there is a group of abnormal cells in an area of the body. However, the number of abnormal cells is too small to form a tumour and may, therefore, be currently classed as benign. The World Health Organisation (WHO) system does not appear to recognise Stage 0 for NETs.
The most generic model for TNM staging is below but please note this could be adjusted for particular types of NET.
Primary Tumor (T) TX: Primary tumor cannot be evaluated T0: No evidence of primary tumour Tis: in situ (abnormal cells are present but have not spread to neighbouring tissue; although not cancer, in situ may become cancer and is sometimes called preinvasive cancer)
T1, T2, T3 and T4 is a measure of the size of, and/or invasion/penetration by, the primary tumour and the wording varies between different NET sites. e.g. for a small intestinal NET:
T1 tumour invades mucosa or submucosa and size <=1 cm
T2 tumour invades muscularis propria or size >1 cm
T3 tumour invades subserosa
T4 tumour invades the visceral peritoneum (serosa)/other organs
Distant Metastasis (M) MX: Distant metastasis cannot be evaluated M0: No distant metastasis M1: Distant metastasis is present
You may occasionally see TNM staging be prefixed by lower case letters. The most commonly used prefix is ‘p’ simply meaning the grading has been confirmed by pathology. e.g. pT4 N1 M1
Specialists can combine the Stage to create a TNM – for example:
This slide will be updated when I get access to WHO 2017 or updated AJCC pubication.
A complex area and I hope I have condensed it sufficiently for you to understand enough for your purposes. Despite looking very scientific, it is not an exact science. There are many variables as there always are with Neuroendocrine disease. NENs can be very challenging for a pathologist even an experienced one who may not have encountered NENs before. However, it is an extremely important part of initial diagnosis and also when needed during surveillance. It is a vital tool used by Multidisciplinary Teams (MDT) in treatment plans and for prognostic purposes. If you need to learn further, I recommend this document:
If you are interested in this subject and have one hour to spare, there is a great video here from LACNETS worth watching.