Reviewed and Updated 13th March 2024

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  The use of the out of date term by both patients, patient advocates and doctors exacerbates the issue given that it decodes to ‘carcinoma like‘ which infers it is not a proper cancer.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 and American Society of Clinical Oncology (ASCO).  I did note some subtle wording differences and I suspect NET patients will appreciated the ASCO version better.

Please note I could have selected a number of organisations but in general, they all tend to be similar. 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 (e.g. Neuroendocrine Tumour of Pancreatic origin 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 considered 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 (2022) and ENETS 2023 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 Neuroendocrine Carcinomas (NEC) are beyond the scope of this discussion.

Malignant tumour – A term used to describe cancer. Malignant cells grow in an uncontrolled way and can invade nearby tissues and spread to other parts of the body through the blood and lymph system..

Benign tumour – Refers to a tumor that is not cancerous. The tumor does not usually 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. e.g, ASCO’s definition: “Benign neoplasm, or benign tumours – a cancer that is not likely to spread, and is contained within one region of the body”. i.e. they do not mean a benign tumour is not cancer. 

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 or malignant. Also called Neoplasm.

Author’s Note: Neoplasm is an interesting term as this is he official overarching term use by the latest WHO Neuroendocrine classification system and covers all Neuroendocrine types of cancer (Tumour (NET) and Carcinoma NEC)). 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 (or should be) internationally recognised classification schemes (i.e. the World Health Organisation (WHO)).
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.

In fact, the WHO classification of tumours in older versions was part of the problem (pre 2010).  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 you can see above.  The wording was tightened up in the 2017 (Endocrine), 2019 (Digestive Systems) and 2021 (Lung/Thymus) publications.  Clearly it took them a while to realise that many types of NET at grade 1 and 2 were metastatic at diagnosis, a clear hint that describing NETs as benign tumours wasn’t the best idea. In 2022, Neuroendocrine Neoplasms now has their own ‘blue book’ grouping almkost every type of NET in one place, helping with naming conventions and greater understanding of the group of tumours as a single entity.  Read more about this ‘neuroendocrine revolution’ below.

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.  In 2022 the first ever WHO Classification system grouping all Neuroendocrinew Neoplasms (NENs) into a single scheme was published   Read more about this by clicking here or on the graphic below.

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).

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 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 functional type of Pancreatic NET). Ditto for Pheochromocytoma (an adrenal gland NET).  This book is out of date with modern thinking – do not quote it!

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, it’s not saying that it’s cancer or will never turn cancerous.  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.  That has been confirmed in many sources as a fairly accurate statistic. 

BUT’ ………  All WHO classification systems sinxw 2010 are based on the concept that NETs always have malignant potential.  The WHO 2017, 2019, 2021, 2022 classification updates all 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.  Although based on statistics, certain primary types need longer surviellance than other types.  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.

The last word

Summary

This was a difficult piece of research. I suspect other slow growing cancers may share the same issues.  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’ in NETs is probably best used with great care and doctors should explain what they mean. 

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:

Carcinoid vs Neuroendocrine

Neuroendocrine Neoplasms – Grading and Staging

Incurable vs Terminal

10 Questions for your doctor and where to find a NET specialist

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