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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 and grade 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 (Neoplasm is technically just another word for tumour and a tumour can be benign or malignant)
- 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 (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 that the classification in the leading picture is to be used for all NENs and that usable extracts will be published shortly by pathology experts. Worth also noting that ENETS 2016 Guidelines are already using the new grading terms.
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 cut-off of 55% could have some influence on the treatment regime.
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.
As far as I can see there are only 2 other publications listing information on the internet in regards WHO 2017 Neuroendocrine Classification and they have been the source material for the 2017 version of this article.
This one from Dr Anthony Gill
This one from Dr Günter Klöppel
(Remember this is based on Endocrine Organs)
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. Often doctors write the stage down in Roman numerals. So you may see stage 4 written down as stage 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.
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 1 tumour is less than 1 cm in size and has not spread to the lymph nodes or other parts of the body
Stage 2 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 3 is any size tumour that has spread to nearby areas of the body and also to at least one lymph node.
Stage 4 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 4 does not necessarily mean a cancer is more dangerous than other cancers of lesser stages. This is an important point for most NETs where Stage 4 can be apparent 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 4 NET, while surgery might not help a patient with different cancer 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
For any T add (m) for multiple tumours
Regional Lymph Nodes (N)
NX: Regional lymph nodes cannot be evaluated
N0: No regional lymph node involvement
N1: regional lymph node metastasis
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.
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:
ESMO Annals of Oncology – Clinical Guidelines for Neuroendocrine gastro-entero-pancreatic tumours (bearing in mind this will not have been updated as per above – other than that it is useful).
You may benefit from reading these associated posts:
Thanks for listening
As I have a 2 year old post about Danielle, I wanted to preface it with this message.
It is with great sadness that I let you know Danielle Tindle passed away at the end of August 2017 after a prolonged battle with Neuroendocrine Carcinoma. She had been fighting cancer in one form or another for 12 years and became passionate in campaigning for more attention for young cancer patients. I’ve been following her story for almost 2 years and she has really inspired me. The title of this article is based on the title of a TV programme about her and her campaign to gain access to new drugs. I had chatted with Danielle online about some of the story below and I hope I’ve interpreted it correctly. RIP Danielle.
I first wrote about Danielle Tindle in Oct 2015 as I was really inspired by her story. Some of you will know that I have a lot of time for inspiring patient stories such as this one. There is no better form of advocacy and awareness than a human being talking about it in front of a camera or microphone. I truly believe these should be at the forefront of international and national campaigns.
Danielle has appeared many times in the national newspapers and TV in Australia. A young person who had gone through gruelling treatments – several chemos and stem cell treatment for get rid of Hodgkin’s Lymphoma. One of her chemo treatments resulted in permanent loss of hair (severe Alopecia) – listen to her very inspirational video by clicking here. She talks about this aspect of her treatment plus many other things. A quote I love is her saying “to be treated like I’m unwell makes me very angry”.
Just when she thought her life was back and near the end of a PhD, they found a Neuroendocrine Tumour in her neck near the larynx which was inoperable and chemo was found to be ineffective. Despite this, she battled on. Her father, a scientist, had coincidentally been involved in the research of an experimental immunotherapy drug, which was at the time being used for Melanoma. Pembrozilumab (KEYTRUDA) has since been approved for a number of cancers including Melanoma, Hodgkin’s Lymphoma, metastatic nonsquamous non-small cell lung cancer (NSCLC); and very recently for advanced or metastatic urothelial carcinoma.
Danielle’s story had also highlighted a growing problem which appears to be causing concern in many countries – the price of drugs which is then compounded by health system processes. How crazy was this ……. Danielle initially wanted to take Pembrozilumab (KEYTRUDA) (made famous by former US President Jimmy Carter) on an experimental basis (……it is not approved for any type of Neuroendocrine Cancer). It would only cost AUS$6 AUS if she was a Melanoma patient but because she has Neuroendocrine Cancer, it cost AUS$5000 a shot for the treatment she needs. You can view the 30-minute ABC ‘Australian Story’ by clicking here
Danielle has confirmed to me that she did eventually try Pembrozilumab (KEYTRUDA) but she was then moved onto a combination of Nivolumab (OPDIVO) and Ipilumumab (YERVOY), also immunotherapy drugs. In fact, the Nivolumab and Ipipumumab did initially make progress with some tumour size reduction – click here. But …….
Unfortunately, from an update gleaned from her ‘gofundme‘ site (Apr 2017), it would appear progress with Nivolumab and Ipipumumab halted, things started to grow and the treatment was stopped. Danielle was then put into palliative care for pain relief. She has had a number of emergency surgeries, including a feeding tube directly to her stomach to eat, and a tracheostomy (a tube that goes into your neck so that you can breathe).
Then a new breakthrough when her oncologist advised that the treatment protocol for immunotherapy had changed and that there may be benefit in continuing to treat her. However, the financial constraints still apply. Despite, Danielle having paid $123,000 for the immunotherapy so far, the drug company has AGAIN denied compassionate access to the treatment.
When I wrote the original blog, I attached a 5-minute video which I personally found very inspiring. She talks eloquently, confidently and she maintains her composure emotionally. She was a brave lady and I’m not sure I could have contained my emotions for the full 5 minutes of the video clip. You can view the video clip here: Click here to view. (Please note this video was recorded before the immunotherapy treatment).
Thanks for reading
The internet is full of blogs and articles about a subject which is described as ‘scanxiety’ – the joining of the words ‘scan’ and ‘anxiety’. I also noted some authors using the words ‘scanxiety’ and ‘anxiety’ interchangeably which in my opinion is clearly wrong.
‘Scanxiety’ – I just don’t get it ……or more accurately I just don’t get overly anxious about scans. Why? Because testing (scans in particular) is the one thing that’s going to keep me alive for as long as possible. I was diagnosed 5 years ago thanks to the trigger of precautionary tests including a scan. I now live with the knowledge (and I accept this fact) that there are still bits of cancer inside me. If I am not regularly tested, there is a chance I will eventually succumb to a serious or irreversible problem which should have been spotted earlier. Even in the event of ‘not so good news’ following a routine surveillance scan, I still see that as a positive because it means the testing has worked and an investigation can be commenced to more accurately localise and treat the problem. Even if you are in the diagnostic phase and a scan is ordered, you need to get right inside that machine and get it over and done with. It just might save your life.
Users of the phrase also extend its meaning to waiting on the results of the scan. I also find this odd as scanning is just one test and just one test result. Thinking back to my own countless appointments either for testing, treatment or for receiving results, I appear to be consistently pragmatic in my approach – the test results will be what the test results will be and I will save any worry until I know if I have anything to worry about.
Many cancer patients are under surveillance for a long time and are tested regularly. As an incurable cancer patient myself, I sometimes feel like I’m in a perpetual state of testing. I suspect if I was to let anxiety get the better of me, that would simply lead to other complications I just don’t need. I’m not that insensitive to forget that some people do probably get anxious about actually climbing into a scanner, particularly if they are claustrophobic but that is already a recognised anxiety issue rather than so-called scanxiety. I also suspect people will be anxious about their relatives having scans, particularly the first diagnostic one, worse when young ones are involved and I totally get that. Anxiety (as opposed to so called scanxiety) is a pretty natural reaction. However, to control your fears, you need to face them and then try not to let your anxiety filter down to others.
Scanxiety – I just don’t get it. As for the 20,300 search results on the internet, I just don’t get that either!
Thanks for listening
So Victoria Derbyshire has breast cancer and has used her ‘workplace’ as a platform to let people know she is a determined survivor. Nothing wrong with that, it’s great cancer awareness for some and inspiration for others (including me). However, reading through various newspaper follow-up articles, blogs and social media comments, I can see criticism by many for producing an over simplified message (see picture below). Although many of us will be wishing it was so, not all cancer is simple!
Take Neuroendocrine Cancer for example. For some, this ‘silent’ cancer can take years to be finally diagnosed whilst the patient is misdiagnosed with other conditions often with debilitating symptoms. Once diagnosed, surgery (if it’s possible) is just one of a number of treatment options and it will often be multiple times. Follow on treatments include an array of biochemical and nuclear options. If the disease is metastatic, which it frequently is due to its years of ‘silence’, then the condition normally becomes incurable and the patient will be treated for the forseeable future, very often with a reduced quality of life. Victoria might not think she had a fight but for many others, this is a particularly apt word – especially those who can never be sure the cancer has gone.
I’m not suggesting that well-known people shouldn’t make their cancer experience public – in fact I’m all for that!
Get well soon Victoria, I really mean that.
I talk often about my diagnosis but not about an ‘incident’ which occurred almost immediately prior to being formally told.
I was well into the ‘diagnostic phase’, having had all sorts of tests including a liver biopsy. I vividly remember thinking these tests were a ‘nuisance’, I was far too busy and I didn’t even feel ill. In hindsight, I was fortunate to have had such a thorough bunch of physicians who diagnosed me with metastatic Neuroendocrine Cancer in about 6 weeks ‘flash to bang’. I intentionally use a phrase associated with ‘quick’ because in the world of Neuroendocrine Cancer, 6 weeks is ‘warp speed’.
So why was I admitted to hospital during the diagnostic phase? Because I was stupid. In fact I was double-stupid. Firstly, despite having had to undergo a liver biopsy and a referral to an Oncologist, I was in a dismissive frame of mind and was blanking out any thought that I actually had cancer. I didn’t have time for it, I was far too busy. I’m in control! Secondly, despite being told to take it easy after the liver biopsy, I ignored that advice because I was far too busy getting on with a normal life. After all, this is just another test hurdle and I’ll get the all clear. Other people get Cancer but not me.
On the weekend following the liver biopsy, the family came round, so I decided to do normal things like lifting one of my grandsons up (as one does) and I prepared the BBQ which involved lifting a 13.5kg cannister of gas from the garage onto the patio. Why not? I didn’t have anything wrong with me and I didn’t even feel ill.
However, as that Saturday afternoon progressed so did the pain; and to the point that I knew I had to seek help. To cut a long story short, I was eventually admitted to hospital for what was to be diagnosed as a bleed on my liver at the biopsy site. Oh how the mighty fall.
On the positive side, I got another bunch of tests including scans as confirmation (….a second opinion from a different hospital). However, it was the wake-up call I needed to take it seriously. I was discharged on the Monday in time for my very first Oncology appointment with my wife Chris in attendance. For the first time, we were officially told I had Cancer – it was much more than just a ‘scare’. For me, the denial was over, indicating that I was never actually in control of what was happening to me.
Finally some food for thought …… In hindsight, I made the serious mistake of not talking to anyone about my denial and I suspect that led to me acting stupidly.
It really is OK to talk about Cancer
p.s. I’m now slightly mellower about Cancer 🙂 You might say I’m back in control?
Thanks for reading
Neuroendocrine Cancers can sometimes present with one or more vague symptoms which occasionally results in a lengthy diagnostic phase for some. Sure, there can be issues with doctor experience and knowledge that can add to the problem. However, some people do present with multiple vague and confusing symptoms and some people have comorbidities which have similar symptoms. Textbook diagnostics just don’t make sense, sometimes even when the doctor suspects Neuroendocrine Cancer i.e. classic symptoms of ‘something’ but with negative markers for NETs. Clearly those are extreme cases and just like other complex diseases, many diagnoses of Neuroendocrine Cancer can be extremely challenging. Even for an experienced doctor, it can be a difficult jigsaw!
Most types of Neuroendocrine Cancer can be accompanied by a ‘syndrome’ i.e. the tumours are ‘functional’ and this is normally (but not always) associated with metastatic disease. At this point it’s also worthwhile saying that some Neuroendocrine Cancers can be ‘silent’ (non-functional) for years before any symptoms show and it’s normally only when they metastasize, that these clinical syndromes come to life. Ironically, the manifestation of the disease with a syndrome can occasionally turn out to be a life saver albeit the cancer is normally incurable at this stage – but still treatable.
The most common type of Neuroendocrine Cancer can often present as a collection of symptoms known as Carcinoid Syndrome and the most common of these is flushing with approximately 84% frequency. Others symptoms include (but are not limited to) diarrhoea, heart palpitations, stomach cramps and general abdominal pain/discomfort, shortness of breath, wheezing. You can see the scope for confusion and misdiagnosis. You may find my blog on the ‘5 E’s of Carcinoid Syndrome’ useful.
When you look at these general Carcinoid Syndrome symptoms, flushing seems to be the one that stands out as a ‘cardinal sign’ whereas many others are vague and easily confused with common/regular illnesses. However, the flushing is reported to be different from most people’s perceptions of a ‘flush’. The Carcinoid flush is almost always ‘dry’. To quote my ‘amazing yellow book‘ (co-authored by Woltering, Vinik, O’Dorisio et al), “…. a good rule of thumb is if the flushing is wet (accompanied by sweating), it is due to a cause other than Carcinoid”. Dr James Yao, another well known NETs guru also raises this distinction by stating…. “The facial flushing of carcinoid syndrome is usually a dry flushing, and not associated with sweating like other kinds of flushing. The flushing is often a symptom that others notice before patients do. They may not feel it themselves.”
Additionally, there appears to be at least two varieties of flushing in Carcinoid Syndrome related to two different anatomical regions of the primary tumour (again a useful guide from my amazing yellow book):
1. Midgut (generally the small intestines (less the duodenal 1st portion), ascending colon, appendix) – faint pink to red in colour, involved face and upper trunk, normally lasts a few minutes and can occur many times per day.
2. Foregut (generally the stomach, lung, thymic and duodenal 1st portion) – more intense, longer duration, purplish, upper trunk and occasionally limbs.
The flushing sympton has many potential triggers and can be attributed to the secretion of excess hormones associated with Neuroendocrine Tumours. Although many people focus on serotonin as the main culprit, there is significant evidence to suggest that other hormones may be playing a bigger part with this symptom, e.g. histamine (particularly foregut), tachykinins (Substance P), bradykinins, and prostaglandins.
If you study the online forums, there are frequent questions about flushing, particularly from those looking for a diagnosis and are suspecting Carcinoid Syndrome due to a flushing symptom. However…… even flushing cannot always be attributed to a NET, particularly if it’s the only symptom being presented.
This is a very useful table taken from my amazing yellow book which gives the tests required to determine the potential source of a flushing (differential diagnosis). I strongly suspect this is not an exact science (…..is anything in medicine?) but it’s extremely useful. Personally I would have included Rosacea 🙂
My own experience with flushing brings back some memories and it emphasises something I say a lot – the patient has a big part to play in their own diagnosis. Please check out this 90 second video about how I did not play my part! I was experiencing a mild and innocuous flushing sensation for some months before I was diagnosed with metastatic Neuroendocrine Cancer. Even though I knew it was weird and something I hadn’t experienced before, I totally ignored it. I failed to mention it at any of my routine GP appointments or my annual asthma clinic. I failed to mention it to my specialist who was investigating a GP/PCP diagnosis of Iron Deficiency Anemia/weight loss. After a CT scan, the specialist appeared to be scratching his head ….. at that point he knew I had cancer but he also knew it was unusual. I suddenly mentioned the flushing and ‘bingo’. It was the face of a man who had just found a missing piece of a jigsaw and he correctly predicted the output from my subsequent liver biopsy.
For the next few months, I was keeping my condition private at work but it was sometimes difficult to disguise the flushing. At least one person thought my blood pressure was going up! Fortunately, my flushing disappeared after treatment.
I’ll complete this post with an interesting summary from an online forum post in which I was participating. There was a general discussion about the severity of ‘syndrome symptoms’ including triggers and I was staggered to read that people were experiencing flushing whilst carrying out routine day-to-day tasks. I’m so happy I don’t flush when I eat one square of chocolate (that would be a complete disaster!). The one which caught my attention was the simple act of washing hair. Whilst I initially raised my eyebrows and laughed, it did make me think back to the last flush I experienced (and touch wood it was the last …..). Following my diagnosis, I commenced daily injections of Octreotide. These injections reduced the flushing but it didn’t eliminate it. However, after my ‘debulking’ surgery in Nov 2010, my flushing disappeared. However, I do remember this small flush coming out of nowhere whilst I was recovering in hospital after that surgery. I was cleaning my teeth and I do vividly remember this minor task taking some effort!
I haven’t had a flush since and if this symptom comes back, I’ll know I have a new problem to contend with.
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