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Ronny Allan
OPINION:
One of the most controversial aspects of Neuroendocrine Neoplasms, in particular low grade Neuroendocrine Tumours (NETs), is the ‘benign vs malignant’ question. It’s been widely debated and it frequently patrols the various patient forums and other social media platforms. It raises emotions and it triggers many responses ….. at least from those willing to engage in the conversation. At best, this issue can cause confusion, at worst, it might contradict what new patients have been told by their physicians (….or not been told). I don’t believe it’s an exact science and can be challenging for a NET specialist let alone a doctor who is not familiar with the disease.
Going forward I’m mostly intending to use the term Neuroendocrine Tumours (NETs) as that is where the problem lies.
NANETS Guidance talks about the ‘…heterogeneous clinical presentations and varying degrees of aggressiveness‘ and ‘…there are many aspects to the treatment of neuroendocrine tumours that remain unclear and controversial‘. I’m sure the ‘benign vs malignant’ issue plays a part in these statements.
In another example, ENETS Guidance discusses (e.g.) Small Intestine Tumours (Si-NETs) stating that they ‘derive from serotonin-producing enterochromaffin cells. The biology of these tumors is different from other NENs of the digestive tract, characterized by a low proliferation rate [the vast majority are grade 1 (G1) and G2], they are often indolent’. However, they then go on to say that ‘Si-NETs are often discovered at an advanced disease stage – regional disease (36%) and distant metastasis (48%) are present‘. It follows that the term ‘indolent‘ does not mean they are not dangerous and can be ignored and written off as ‘benign’. This presents a huge challenge to physicians when deciding whether to cut or not to cut.
Definitions
To fully understand this issue, I studied some basic (but very widely accepted) definitions of cancer. I also need to bring the ‘C’ word into the equation (Carcinoid), because the history of these tumours is frequently where a lot of the confusion lies. The use of the out of date term by both patients, patient advocates and doctors exacerbates the issue given that it decodes to ‘carcinoma like‘ which infers it is not a proper cancer. See more below.
Let’s look at these definitions provided by the National Cancer Institute. Please note I could have selected a number of organisations but in general, they all tend to agree with these definitions give or take a few words. These definitions help with understanding as there can be an associated ‘tumour’ vs ‘cancer’ debate too.
Cancer – Cancer is the name given to a collection of related diseases. In all types of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues. There are more than 100 types of cancer which are usually named for the organs or tissues where the cancers form. However, they also may be described by the type of cell that formed them.
Author’s note: The last sentence is important for Neuroendocrine Tumour awareness (i.e. Neuroendocrine Tumour of the Pancreas rather than Pancreatic Cancer).
Carcinoma – Carcinomas are the most common grouping of cancer types. They are formed by epithelial cells, which are the cells that cover the inside and outside surfaces of the body. There are many types of epithelial cells, which often have a column-like shape when viewed under a microscope.
Author’s note: By definition, Carcinomas are malignant, i.e. they are without question malignant cancers. Poorly differentiated Neuroendocrine Neoplasms are deemed to be a ‘Neuroendocrine Carcinoma’ according to the most recent World Health Organisation (WHO) classification of Neuroendocrine Tumours (2017) and ENETS 2016 Guidance. You will have heard of some of the types of Carcinoma such as ‘Adenocarcinoma’ (incidentally, the term ‘Adeno’ simply means ‘gland’). It follows that Grade 3 Neuroendocrine Carcinomas (NEC) are beyond the scope of this discussion.
Malignant – Cancerous. Malignant cells can invade and destroy nearby tissue and spread to other parts of the body.
Benign – “A growth that is not cancer. It does not invade nearby tissue or spread to other parts of the body”.
Author’s Note: This is a key definition because doctors are trained to use that word for any cancer meeting that definition.
Tumour (Tumor) – An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancer), or malignant (cancer). Also called Neoplasm.
Author’s Note: Neoplasm is an interesting term as this is what is frequently used by ENETS and NANETS in their technical documentation, sometimes to cover all Neuroendocrine types of cancer (Tumor and Carcinoma). It follows that a malignant tumour is Cancer. The term “Malignant Neuroendocrine Tumour” is the same as saying “Neuroendocrine Cancer”
This is the language doctors use, this is the language they are trained to use but it doesn’t always work out in our favour in real life.
Neuroendocrine Tumours – Benign or Malignant?
Definitions out of the way, I have studied the ENETS, UKINETS and NANETS guidance both of which are based on internationally recognised classification schemes (i.e. the World Health Organisation (WHO)).
In older versions of the WHO classification schemes (1980 and 2000), the words ‘benign’ and ‘uncertain behaviour’ were used for Grades 1 and 2. However, in the 2010 digestive systems edition, the classification was fundamentally different (as is the recent 2017, 2019 and 2021 publications). Firstly, it separated out grade and stage for the first time (stage would now be covered by internationally accepted staging systems such as TNM – Tumour, (Lymph) Nodes, Metastasis). Additionally, and this is key to the benign vs malignant discussion, the WHO 2010 digestive system classification is based on the concept that all NETs have malignant potential. Here’s a quote from the UKINETS 2011 Guidelines (Ramage, Caplin, Meyer, Grossman, et al).
Tumours should be classified according to the WHO 2010 classification (Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010). This classification is fundamentally different from the WHO 2000 classification scheme, as it no longer combines stage related information with the two-tiered system of well and poorly differentiated NETs. The WHO 2010 classification is based on the concept that all NETs have malignant potential and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential.
The guidance from the World Health Organisation (WHO) in 2016 (Head and Neck Paraganglioma) and 2017 (Endocrine Systems) WHO reinforces this statement to include endocrine organs, including the pancreas and adrenal glands. And the 2019 edition of Digestive Systems (now effectively all GEPNENs) reinforced these issues and for the first time added pancreatic NETs, previously covered in Endocrine organs, effectively giving us a ‘Blue Book’ for Gastroenteropancreatic NETs (GEPNETs). It also removed the term ‘Carcinoid’ a huge part of our awareness and understanding issue.
The C Word (Carcinoid) – part of the problem?
History lesson – Carcinoid tumours were first identified as a specific, distinct type of growth in the mid-1800s, and the name “karzinoide” was first applied in 1907 by German pathologist Siegfried Oberndorfer in Europe in an attempt to designate these tumours as midway between carcinomas (cancers) and adenomas (benign tumours).
The word ‘Carcinoid’ originates from the term ‘Carcinoma-like’. ‘CARCIN’ is a truncation of Carcinoma. ‘OID’ is a suffix used in medical parlance meaning ‘resembling’ or ‘like’. This is why many people think that Carcinoid is not a proper cancer.
The situation is made even more confusing by those who use the term “Carcinoid and Neuroendocrine Tumors” inferring that it is a separate disease from the widely accepted and correct term ‘Neuroendocrine Tumour’ or Neuroendocrine Neoplasm. A separate discussion on this subject can be found in this post here.
I encourage you to stop using the term ‘Carcinoid’ which is just perpetuating the problem. You should also ask your local patient advocate organisation and your doctor to cease its usage too (including in organisational naming).
How are NENs Classified?
If you read any NET support website, it will normally begin by stating that Neuroendocrine Neoplasms constitute a heterogeneous group of tumours. This means they are a wide-ranging group of different types of tumours. However, the latest WHO classification system uses the terms ‘Neuroendocrine Tumour’ for well-differentiated Grade 1 (low-grade), Grade 2 (Intermediate Grade), and Grade 3 (High Grade) NET; and ‘Neuroendocrine Carcinoma’ (NEC) for poorly differentiated tumours which are by default grade 3 or high grade. They also use the term ‘Neoplasm’ to encompass all types of NET and NEC. So, Grade 1 is a low-grade malignancy, and so on (i.e any grade of NET is a malignant tumour). You may benefit from reading my blog article on Staging and Grading of NETs as this is also a poorly understood area.
There are different classification systems for Pheochromocytoma and Paraganglioma introduced in 2017 (updated in 2022) and based on the WHO ‘blue book’ for “Endocrine Systems” These grades are based on molecular profiles (the future way for many cancers and the first time for a NET). They have a system of grading called GAPP (grading of adrenal pheochromocytoma and paraganglioma) and they are clustered into the metastatic risk (this is the beauty of molecular methods). So, they are different than regular NETs and they now have 3 differentiations, loosely related to grade. It’s much more complex. Read more about classification systems here.
Can some NETs be Benign?
By any accepted definition of cancer terms, a tumour can be non-cancerous (benign) or cancerous (malignant). This is correct for any cancer type. Before the 2010 WHO changes, many texts remain out of date (or stick to the principles of classic cancer definitions. One example is the current (2016) version of Inter Science Institute (ISI) publication on Neuroendocrine Tumors, a document that many US patients reference (but it’s clearly now out of date). For example, I’ve seen statements such as “These tumors are most commonly benign (90%)” in relation to Insulinoma (a type of Pancreatic NET or pNET). Ditto for Pheochromocytoma (an adrenal gland NET). Adrenal and Pituitary ‘adenomas’ are by definition benign (adenoma is the benign version of Adenocarcinoma). And I note that there is a ‘benign’ code option for every single NET listed in the WHO International Classification of Diseases (ICD) system. BUT remember the widely used definition of Benign I gave above. Benign means the tumour does not invade nearby tissue or spread to other parts of the body. So, for example, when the ISI states “90% of insulinomas are benign”, they are saying that 90% of them do not invade nearby tissue or spread to other parts of the body.
Here’s another ‘BUT‘ ……… but all WHO classification systems are based on the concept that NETs always have malignant potential. The WHO 2017, 2019, 2021, 2022 classification updates confirm this thinking.
Can Tumours be Malignant or become Malignant?
Using the definition above, if a tumour invades and destroy nearby tissue and spread to other parts of the body, then it’s malignant (i.e Cancer). However, there’s a reason why the WHO declared in 2010 that all NETs have malignant potential (as amplified in WHO 2017 onwards). It may not happen, or it may happen slowly over time but as Dr Richard Warner says, “they don’t all fulfil their malignant potential, but they all have that possible outcome”. Thus, why ongoing surveillance is important after any diagnosis of Neuroendocrine Tumour of any grade or at any stage. Dr Lowell Anthony, a NET Specialist from the University of Kentucky explains this much better than I can – Click here to hear his two-minute video clip.
This issue even caused confusion with doctors if statements made in my patient group are accurate. Apparently, some of them still think a Stage 4 NET is benign. Not only is this very insensitive to the patient concerned but it also goes against all the definitions of ‘benign’ and ‘malignant’ that exist in authoritative texts, some quoted above. Just as insensitive as telling a patient that Neuroendocrine Tumours are not really cancer.
Summary
This was a difficult piece of research. I do believe there are scenarios where NETs will be benign and probably never cause the person any real harm (e.g. many are found on autopsies). I suspect this is the same for many cancers. However, based on the above text and the stories of people who have presented for a second time but with metastatic disease, use of the word ‘benign’ is probably best used with great care.
I would certainly (at least) raise an eyebrow if someone said to anyone with any NET, “you don’t need any treatment or surveillance for a NET”; or “it has been cured and no further treatment or surveillance is required”. Particularly if they are not a NET specialist or a recognised NET Centre.
Remember, I’m not a medical professional, so if you are in any doubt as to the status of your NET, you should discuss this directly with your specialist. A good place to start is evidence of your Grade, Differentiation, Primary Site Location and Stage.
You may be interested in reading these associated posts:
Neuroendocrine Neoplasms – Grading and Staging (WHO 2021)
10 Questions for your doctor and where to find a NET specialist
Disclaimer
I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.
Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional.
Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.
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Any updates to this article since you originally posted? Perhaps more data on the benign side of the equation- G1 well-diff stage 1 tumors verified by biopsy with Ki67 < 2%? Any of those kinds of “early stage” patients being monitored with regular NET specific scans, without any treatment, and remaining static for entirety of patient’s life?
That very much depends on your doctors, I.e. where the primary is as some NETs are known to metastasise more than other types. Plus what guidelines they use (often country specific)
I have neuroendocrine cancer and a growth just showed up on my adrenal gland. what is the chance this growth could be benign.
Difficult to say. Where is your primary tumour?
Hi, I was diagnosed with Neuroendocrine rectol tumor Dr. says is small and benign. Going to do more tests. Everything I read tells me 5 years to live. I just turned 60
The Dr. said he thought he removed it all. Is this a death sentence? Do I have 5 years to live ?
The outlook for rectal NETs is very good. They very rarely spread. Go live your life.
https://ronnyallan.net/2019/11/17/prognostics-and-crystal-balls/
Ronny do you need me to give a clearer story. Gaynor
no I have enough thanks
I have went misdiagnosed for 7 years effects my heart went to spine brain and because I caught dr’s lying through emails I’m not getting any treatment also in liver and pancreas went to go to gp asked to see oncologist she won’t refer me hospital won’t give me copy of disc. And she wants me to go and see people who misdiagnosed me in the first place. She said I could pay private and they would say anything so everyone is closing rankes. Flighting for my life and no one is listening.
Hi Ronny
To say I enjoy reading your blogs would be incorrect due to the nature of the beast, but I do find them easy to follow and understand. I have pancreatic primary leading to liver mestates which is still hanging around despite 2 resections. They dont scare me anymore after all, i am bigger than them and have a lot of people on my side. I dont think or ask how long have I got but more what shall i do today that is fun and makes me happy. Thank you so much for taking time out to help us understand better what is going on inside our bods. I am sure i speak for all your readers who really appreciate what you do. You should write a book! I would definately buy!!
Great comment, thank you so much. Can I use parts of this quote in my publicity please?
Of course you may 😀
Thankyou again Ronny. Your writing is so much easier to understand
Thanks. I have read a lot about NETS and this cleared up some confusion I had. There were things I did not know.
Thank you for doing the hard work and explaining things so clearly, Ronnie! This is the best explanation of the difference between benign and malignant that I have ever heard. As it pertains to NETS, this is information that definitely needs to be made better known. A couple of years ago, when I visited our local hospital emergency room for an issue completely unrelated to my NETS, the attending doctor, a locum, actually argued with me about whether or not I had cancer when I told him that I was a NETS patient!
Your words are always so well written and easy to understand. Thank you, again and again.
Laurie – that is such a good comment – I wondered if I could use that on my blog home page? I’ll just refer to you as Laurie if that’s OK?
Great explanation, Ronnie! Thanks, Jean Borden