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 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
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 is important as they are both 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 (common in NETs). I’m also including information on something known as ‘differentiation’ as this is also a key point for NETs grading.
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.
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. Tumours 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. 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 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 is normally referred to as Neuroendocrine Carcinoma indicating it is a faster growing and more aggressive cancer. In 2017, high grade NENs were divided into two classes based on their differentiation (see below).
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 NET pathology experts. Worth also noting that ENETS 2016 Guidelines have already been using the new grading terms.
The 2017 World Health Organisation (WHO) classification sub-divided Grade 3 into two new entities: 3a – a well differentiated high-grade and 3b – 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 3a (NET) and Grade 3b (NEC) have the same biopsy marker cut-offs as per the leading slide but it is thought that a cut-off of 55% could influence 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 are not automatically classified as Grade 3a or 3b/High Grade.
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.
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).
Thanks for reading
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