Understanding Neuroendocrine Cancer
Each year in the UK, around 6,000 people are diagnosed with a Neuroendocrine Cancer. It can occur in people of any age or gender and can develop in many places throughout the body – but what exactly is Neuroendocrine Cancer?
In this section you can find up to date and reliable information about:
The Endocrine and Neuroendocrine Systems.
Communication between cells and tissues of the body, is essential to maintain normal body functions. The complex systems responsible for this are the Endocrine and Neuroendocrine systems.
Press play to watch this short animation about the Endocrine and Neuroendocrine systems.
What is Neuroendocrine Cancer
Cancer is a condition where cells within the body start to grow and reproduce uncontrollably. These cells can invade and destroy surrounding healthy tissue, including organs and some can spread to other parts of the body (metastasise).
Neuroendocrine cancers occur when neuroendocrine cells stop working normally and start to grow uncontrollably and / or function abnormally.
For further information please download our ‘The Science Behind Neuroendocrine Cancer’ guide, which includes information about the Neuroendocrine and Endocrine System, causes and how Neuroendocrine Cancers are formed. But remember – if you are concerned, or would like to talk to a member of our helpline team – please get in touch.
Staging and Grading
Looking at where your neuroendocrine cancer is can tell us whether it is ‘early stage’ (limited to the area in which it starts) or ‘advanced’ (has spread to other places in the body).
Staging is usually assessed by scans and/or histology.
Commonly, there are four stages – but the criteria for each stage can vary depending on the primary site:
- Stage I: the cancer is confined to the area in which it starts
- Stage II: cancer has spread to locally surrounding cells or tissue
- Stage III: cancer has spread beyond surrounding tissues and to nearby lymph nodes
- Stage IV: cancer has spread to another place within the body, including lymph nodes.
Click here to find out more about your primary cancer site.
Two key factors can help accurately grade neuroendocrine cancer:
- differentiation: which refers to cell appearance
- mitotic rate: which refers to how quickly or slowly cancer cells are dividing and growing
Differentiation refers to how different the cancer cell looks compared to what it should look like as a normal cell. Using this information, it is possible to divide neuroendocrine cancers into two main groups: neuroendocrine tumours or neuroendocrine carcinomas.
Neuroendocrine Tumours (NETs) are well-differentiated cancers. This is because although abnormal, with evidence of cancerous change, the neuroendocrine cancer cells that form the tumour have kept many of the characteristics of a normal neuroendocrine cell. Their mitotic rate can vary from slow to rapid.
Neuroendocrine Carcinomas (NECs) are poorly-differentiated cancers. This is because the neuroendocrine cancer cells have become very abnormal, with obvious features of cancerous change, losing many of the features of a normal neuroendocrine cell. They are also distinct by cell size – and can be further classified as either small cell or large cell carcinomas. Their mitotic rate is consistently high.
Mitotic rate: measures how fast cancer cells are dividing and growing. To find the mitotic rate, the number of cells actively dividing in a certain amount of cancer tissue is counted. This may be reported in histopathology reports using the abbreviation MiB-1 or Mitoses per 10 HPF. However, for most neuroendocrine cancers, histopathologists use Ki67 to ‘stain’ or identify actively dividing cancer cells.
You may see the term Ki67 followed by a percentage used in your clinical letters or reports.
Ki67 is a protein that is present during all of the active stages of the cell cycle, a valuable marker of proliferation (cell division and growth), often expressed as a percentage(%). The higher the Ki67%, the more rapidly the cells divide and grow.
Broadly speaking there are 4 grading categories of Neuroendocrine Cancer:
- Grade 1 is a well-differentiated cancer with a Ki67 less than 3%
- Grade 2 is a well-differentiated cancer with a Ki67 between 3 and 20%
- Grade 3 is a well-differentiated cancer with a Ki67 more than 20%
- The 4th category is NEC – a poorly-differentiated cancer with a Ki67 more than 20%, often above 50%.
Ki-67 staining of neuroendocrine cancer:
- grade 1 NET (ileum)
- grade 2 NET (lung, atypical carcinoid)
- grade 3 NET (pancreas)
- NEC (small cell lung cancer).
However, the exact cut-off criteria between G1-3 NETs may differ depending on the primary site. For example, in Lung, where well-differentiated tumours are often referred to as either Typical or Atypical Carcinoids rather than NETs – the cut-off is:
- Typical Carcinoid: A well-differentiated Lung neuroendocrine cancer with a Ki67 of less than 5% would be considered low-grade.
- Atypical carcinoid: A well-differentiated Lung neuroendocrine cancer with a Ki67 between 5 – 30% may be considered moderate-grade.
- NEC: poorly-differentiated, either small or large cell carcinomas, with a Ki67 of more than 30%.
(Source: La Rosa (2023) Endocrine Pathology (2023) 34:79–97)
The importance of accurate grade cannot be over-emphasised as it is a key determinant of both treatment planning and decision-making, alongside prognosis (where the prognosis is the prediction of the most likely course of the disease as well as the treatment response).
Differentiation, Functioning and Non-Functioning
What does it mean by ‘differentiation’?
Differentiation describes how much or how little cancer cells looks like the normal cells it came from.
- Well-differentiated cancer cells look more like normal cells under a microscope and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells.
- Poorly or undifferentiated cancer cells, when examined under a microscope, have lost many features of the normal cell they once were and tend to grow and spread more quickly than well-differentiated cancer cells.
Functioning & Non-Functioning
Functioning or Non-functioning refers to the hormone or chemical production and release by Neuroendocrine Cancer cells.
Functioning neuroendocrine cancer cells produce and release abnormal, that is higher, amounts of the hormone or chemical they are usually responsible for.
Non-functioning neuroendocrine cancer cells usually retain their ability to release normal amounts of hormone or chemical.
This abnormal release can result in symptoms and / or syndromes. For more information about Syndromes click here.
N.B. Functioning may also be used as a term to describe whether your cancer is ‘positive’ on scans, that is, can it be seen on ‘functional imaging’ such as Octreotide, MiBG, Gallium and / or FDG-PET scans.
Is Neuroendocrine Cancer genetic?
Most Neuroendocrine Cancers occur ‘sporadically’, this means that there is no known genetic link to how or why they have developed.
However, there are a number of rare genetic conditions that may increase someone’s risk of developing a Neuroendocrine Cancer – these include:
- Multiple endocrine neoplasia (MEN) types 1, 2, and 3
- Medullary thyroid cancer (MTC), familial medullary thyroid cancer (FMTC)
- Adrenal gland based tumours (phaeochromocytomas & paragangliomas)
- Parathyroid hyperplasia
- Familial isolated pituitary adenoma (FIPA)
- Succinate dehydrogenase (SDH) disorders.
Further information about these disorders can be found at www.amend.org.uk
Primary & Secondary Neuroendocrine Cancer
Primary site refers to where your Neuroendocrine Cancer started to grow.
Primary site matters because it can influence how and why symptoms may occur. It can also make a difference to what treatment is used – for example, whether surgery is possible or not, due to position of tumour and whether surrounding tissue or structures may be affected.
Click here to find out more about your cancer primary site.
What happens if my cancer spreads?
What is secondary Neuroendocrine Cancer?
The terms ‘metastatic’ or ‘secondary cancer’ both refer to the spread of cancer cells from the place where they first formed (primary site) to another part of the body.
In metastatic or secondary disease, the cancer cells break away from the original (primary) cancer, travel through the blood or lymph system, and form a new site of disease in other organs or tissues of the body. This new site is called a metastasis or secondary site – and will be formed by the same kind of cancer cells as those found in the primary site.
For example – if your primary site is the small bowel and you have metastases in the liver – the metastases will be formed by cancer cells from the small bowel, rather than liver cells.
Download our ‘Secondary Neuroendocrine Cancer’ factsheet to learn more.
Different neuroendocrine cancers affect people in different ways depending on where they are, how slowly or rapidly they are growing, their differentiation, whether they are functioning or non-functioning, whether they are associated with symptoms or not, what stage they are at and whether they have a genetic link or not.
They can also appear to behave differently when other factors are in play, for example; other health conditions, age, access to expert healthcare, treatments, responses to treatment and decisions made regarding care and treatment.
Although neuroendocrine cancers may share similar characteristics, the diagnosis and the way the cancer may behave can be different between people – even if they have the same diagnosis.
Syndromes, Hormones, Complications & Highgrade
Neuroendocrine Cancer-related Syndromes occur when Neuroendocrine Cancer cells undergo changes that result in the abnormal production and excessive release of specific peptides and hormones. These syndromes are present in about 40% of Neuroendocrine Tumours but are rare in Neuroendocrine Carcinomas. This guide covers various Neuroendocrine Cancer-related syndromes, including:
- Carcinoid Syndrome (involving serotonin, histamine, and kinins)
- Pheochromocytoma and Paraganglioma
- Zollinger-Ellison Syndrome
- Clinical Hypoglycemia
- Werner-Morrison Syndrome
- Glucagonoma Syndrome.
Additional syndromes mentioned are GHoma, PTHrPoma, ACTHoma, Calcitoninoma, Neurotensinoma, PPoma, and Somatostatinoma.
High Grade Neuroendocrine Carcinomas
Select play to watch Dr Nick Coupe, Medical Oncologist, Oxford University Hospital NHS Foundation Trust talks to Neuroendocrine Cancer UK about high grade neuroendocrine carcinomas.
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