Neuroendocrine Neoplasms – Grade and Stage (incorporating WHO 2017 changes)


Grades of Neuroendocrine Tumour WHO 2017 15 Dec 2017

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

NEN Breakdown

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 less than 55% might benefit from the same treatment given to poorly differentiated NEC. 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 (spread)

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.

Notes:

  • 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 or updated AJCC pubication.

Summary

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.

Finally – always make sure you get your pathology results at diagnosis and following any subsequent sampling.

You may benefit from reading these associated posts:

Benign vs Malignant

Incurable vs Terminal

Carcinoid vs Neuroendocrine

10 Questions for your doctor

Thanks for listening

Ronny

I’m also active on Facebook.  Like my page for even more news. Please also support my other site – click here and ‘Like’

Disclaimer

My Diagnosis and Treatment History

Most Popular Posts

Sign up for my twitter newsletter

Check out my Podcast (click and press play)

Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

patients included
This is a Patients Included Site

WEGO Awards

23 thoughts on “Neuroendocrine Neoplasms – Grade and Stage (incorporating WHO 2017 changes)

  1. Teri Kerr May 22, 2018 / 14:08

    Thank you this is every informative

    Liked by 1 person

  2. RoamingRAVE Wilkinson August 1, 2017 / 00:21

    My small intestine NETs was well-differentiated and therefore considered low grade but my TNM staging was 111b as it had metastasised to the lymph nodes. Despite open surgery to remove the tumour(s), I was put on a wait and see plan afterwards and given no dietary follow up, no access to a NET nurse, or any cancer nurse, no exercise plan and no support information. It’s been a 10-month journey to find my way with all this while trying to recover from horrendous surgery. Awful, but I’m getting there thanks to blogs like yours, to discovering the Australian Cancer Council, a NETs nurse at a capital city hospital who has allowed me to be on her closed network site to get info. It really is a joke! Top top it off because I present OK, my family think my cancer diagnosis must have been wrongly diagnosed and I’m cured. Sigh

    https://polldaddy.com/js/rating/rating.js

    Liked by 1 person

    • Ronny Allan August 1, 2017 / 07:23

      I could write a blog post based on your comment! Clearly i wouldn’t mention your name or even your country if origin. TNM ….. what is 111b? Never seen it described like that …..

      Like

  3. Anne December 21, 2016 / 14:29

    Ronnie, this post is one I read again and again for reassurance! Your ability and willingness to make these diagnosis terms understandable is heart warming. You break the cancer mumbo jumbo down into phrases I can hold onto and find encouragement. Thank you.

    Liked by 1 person

  4. Dean Robertson September 15, 2016 / 06:27

    Ronny, what percentage of patients are low, intermediate and high grade. Love your blog, the only one worth reading

    Liked by 1 person

    • Ronny Allan September 15, 2016 / 07:53

      You made me work with that great question. Information is sparse and I can see it is very location dependant. For example, nearly all NETS of the esophagus are Grade 3 but hardly any of the appendix are. I did find one study of 773 patients broken down to 16% grade 3, 10% grade 2, 74% grade 1. Thanks for the kind words.

      Like

      • Dean September 16, 2016 / 00:30

        Thanks Ronny it’s just so confusing you go from the one extreme,oh that’s nothing you just take a couple injections to that’s what killed Steve Jobs no wonder people are confused

        Liked by 1 person

      • Ronny Allan September 16, 2016 / 07:50

        Yes, it’s not easy, but stick with me, my aim is to help decode these things into something patients can understand.

        Like

      • Dean September 18, 2016 / 10:03

        Cheers Mate

        Liked by 1 person

      • Dean September 19, 2016 / 01:21

        Ronnie I see that you’re Scottish from the Facebook page.
        I was born in Edinburgh although I live in NYC now . Missed my trip this year due to illness but I’ll be there next year at the Sheeps Heid having a pint

        Liked by 1 person

      • Ronny Allan September 19, 2016 / 07:11

        I’m a Dundee man. Now living in the south of England. I go up once a year, in fact just been up and drove the new route NC500 and went to the tattoo. See you in the Sheep’s Heidi 😃

        Like

    • Ronny Allan May 17, 2016 / 21:06

      Thanks for letting me know. I recently criticised it for containing a major error to perhaps someone took my complaint seriously. Thanks again.

      Like

  5. Christine Craig October 29, 2015 / 12:50

    Thanks tried to understand this for 5 years. Well done.

    Liked by 1 person

  6. Tony Reynolds October 28, 2015 / 14:38

    Reblogged this on Tony Reynolds Blog and commented:
    If you are not some sort of hermit at some point in your life you are going to come in contact with a friend or relative who has cancer. This helpful blog that is looking at a particular type of cancer equips you with basic understanding of ‘Doctor Talk’ in the area of cancer, really worth spending a few minutes and reading!

    Liked by 1 person

  7. Ed October 28, 2015 / 13:56

    Ronny, I have tried to blog about this exact thing multiple times but could not get a handle on it. Thanks for such a concise and clear summary! ~ Ed

    Liked by 2 people

      • Ed October 28, 2015 / 18:50

        This will be another Ronny Allan post that I will have to read more than one time and slowly at that! 😀

        Liked by 2 people

  8. cy October 27, 2015 / 21:25

    Ronny,
    Excellent conversion of doctor speak to patient lanquage. I find that even people who have had the disease for a long time misunderstand and misuse these terms. Many physicians seem to misunderstand and misuse as well.

    Good job!
    Cy

    Liked by 2 people

Thanks for the comment, make sure you have ticked the box to receive notifications of responses

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.