Neuroendocrine tumours: an overview

By Cristiano Antonino On Nov 27, 2022

Neuroendocrine tumours account for less than 0.5% of all malignant tumours

In Italy, according to AIOM data, there are 4-5 new cases per 100,000 people every year, with approximately 2,700 new diagnoses.

What are neuroendocrine tumours?

They are rare diseases, very different in terms of location and aggressiveness, generally characterised by slow growth, which originate from the cells of the neuroendocrine system and can affect various organs such as the intestine, pancreas, lungs, thyroid, thymus or adrenal glands.

These neuroendocrine tumours share certain biological features that in many cases allow specialists to use similar strategies for diagnosis and treatment.

A minority of neuroendocrine tumours localised in the gastro-enteric-pancreatic tract consist of poorly differentiated, fast-growing tumour cells, which may originate from all districts, and which require differentiated treatment compared to other forms of neuroendocrine tumours.

Neuroendocrine tumours differentiate into functioning, i.e. stimulating the excess production of hormonal substances responsible for various symptoms, and non-functioning, i.e. not exerting this stimulus.

What are endocrine tumours of the pancreas?

Among the neuroendocrine tumours, those called endocrine tumours of the pancreatic islets (or pancreas) account for 5-10% of pancreatic tumours: these are neoplasms that originate from aggregates of endocrine cells in the pancreas, where they are localised, but can also arise in the duodenum.

As with other neuroendocrine tumours, pancreatic endocrine tumours are distinguished between ‘functioning’, which is rarer, and non-functioning, which is more frequent.

Functioning pancreatic endocrine tumours are:

Insulinoma: this is the most frequent; it produces an excess of insulin, the hormone that regulates glucose (sugar) values in the blood.
Gastrinoma: this type of tumour produces gastrin, a hormone that increases acid production by the stomach.
Glucagonoma: this rare type of tumour produces glucagon.
Somatostatinoma: particularly rare and secretes somatostatin.
VIPoma: causes increased production of vasoactive intestinal peptide (VIP), a hormone that controls the secretion and absorption of water by the intestine.

What are the risk factors for neuroendocrine tumours?

The risk factors associated with the onset and development of neuroendocrine tumours are still not entirely clear.

However, there is a recognised familiarity for Multiple Endocrine Neoplasia Type 1 (MEN 1) syndrome, a rare genetic disorder that can cause the occurrence of several types of neuroendocrine tumours such as pancreatic cancer, parathyroid tumours and pituitary gland tumours, with production of different hormones and consequent hormonal syndromes.

What are the symptoms of neuroendocrine tumours?

The signs and symptoms of neuroendocrine tumours differ depending on the hormone produced by the functioning tumour and the size of the tumour mass, especially in non-functioning tumours.

The main symptoms caused by functioning neuroendocrine tumours are:

onset of diabetes
hypoglycaemia (low blood glucose levels)
cholelithiasis (gallstones)
duodenal ulcers
diarrhoea.

Specifically, Insulinoma is characterised by:

hypoglycaemia
feeling of fainting
dizziness
sweating
tachycardia
reduced blood glucose levels.

Gastrinoma, on the other hand, causes stomach ulcers and diarrhoea; glucagonoma causes diabetes and skin rash; somatostatinoma causes diabetes, gallstones and difficulty digesting fatty foods; VIPoma is characterised by profuse diarrhoea.

The main symptoms caused by non-functioning neuroendocrine tumours are:

pain
jaundice
weight loss
vomiting

How are neuroendocrine tumours diagnosed?

The discovery of a neuroendocrine tumour often occurs during diagnostic tests performed for other reasons or following suspicious symptoms.

In order to confirm the diagnostic suspicion, identify the exact location of the tumour, its size and possible spread to other organs, and assess whether it can be surgically removed, diagnostic laboratory tests (based on the clinical suspicion) and instrumental tests are required, such as

Blood tests: may reveal increased levels of specific hormones such as insulin, gastrin, glucagon, or other substances produced by the tumour, particularly chromogranin A, a protein produced by endocrine tumours in general.
Computed tomography (CT) of the abdomen using a triphasic technique: this allows accurate images and information on whether the tumour has spread to the lymph nodes or liver to be acquired, thanks to the passage of the contrast medium during three different phases through the liver.
Magnetic resonance imaging (MRI) of the abdomen.
Echoendoscopy: allows accurate visualisation of the pancreas through the gastric and duodenal walls and taking small samples of the tumour (needle aspiration) for analysis, thanks to a thin, flexible endoscope to which a small ultrasound probe is attached, which reaches the stomach and duodenum through the mouth.
PET-CT (Positron Emission Tomography with CT fusion): thanks to the development of specific radiopharmaceuticals for neuroendocrine tumours, it is currently one of the fundamental investigations for the diagnosis and restadition of these tumours. On the basis of the radiopharmaceutical used, PET-CT can be distinguished into:
PET-CT with FGD: the radiopharmaceutical used accumulates in tumour lesions characterised by high sugar metabolism, making it possible to provide information on the aggressiveness of neoplasms.
PET-CT with Dopamine: uses a precursor of certain substances secreted by neuroendocrine tumours to identify the metabolism characteristic of each type of tumour.
PET-CT with Gallium-DOTA-peptide: uses a radiopharmaceutical which, by binding to somatostatin receptors very often present in abundance on the surface of neuroendocrine tumours, allows the study of the receptors of these neoplasms, identification and selection for certain types of therapies using somatostatin analogue radiopharmaceuticals.
Receptor scintigraphy: allows neuroendocrine tumours to be detected by the presence of somatostatin receptors, but is an investigation considered obsolete in centres where PET-CT with Gallium-DOTA is available.
Biopsy: this is the taking of tumour tissue for examination at a later date, which is essential in order to determine whether it is a poorly differentiated neuroendocrine carcinoma.
Genetic analysis for MEN1 syndrome.

What are the treatments for neuroendocrine tumours?

Given their heterogeneity, treatment for neuroendocrine tumours is often multidisciplinary and may involve various combinations of treatment.

In particular:

Surgery

Surgical removal of the tumour is the treatment of first choice, and the most effective.

In particular, pancreatic neuroendocrine tumours located in the pancreas and duodenum can be surgically removed with operations that are often less demolitive than those performed for pancreatic carcinoma.

Among the various surgical techniques performed for the removal of neuroendocrine tumours, on the basis of specialists’ assessments, is laparoscopy, with a minimally invasive approach that can reduce pain and postoperative length of stay.

Oncological treatment

Hormonal therapy: depending on the extent and biological and histological features of the disease, hormonal therapy with monthly injections of a somatostatin analogue (octreotide or lanreotide) may be proposed.

This therapy makes it possible to control not only the symptoms but also the evolution of the disease by allowing it to become chronic.

Chemotherapy: cytotoxic chemotherapy treatment can be used in low-grade advanced disease that does not respond to hormone therapy or in more aggressive histological forms in oral and/or intravenous form.

A valid alternative approved in the last 10 years is target therapy (Everolimus or Sunitinib), biological therapies that act on a molecular target expressed by the tumour.

Radiotherapy

Radiometabolic or radioreceptor therapy

Given the high density of somatostatin receptors on the surface of neuroendocrine tumours, radioreceptor therapy exploits the action of a somatostatin analogue drug – and thus with an abundance of related receptors on tumour cells -, which, labelled with a radioactive portion (yttrium or lutetium), is able to recognise its ‘target’ thanks to the binding of the somatostatin analogue to the receptors present on the neoplasm.

Injected intravenously, the radiopharmaceutical is able to target those tumour cells to which the radiopharmaceutical has bound.

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