Neuroendocrine tumour

• What is Neuroendocrine Tumour?
• Statistics
• Risk Factors
• Progression
• Symptoms
• Clinical Examination
• How is it Diagnosed
• Prognosis
• Treatment
• References

What is Neuroendocrine Tumour?

Neuroendocrine tumours (NETs) are tumours composed of neuroendocrine cells, which are cells that produce and secrete regulatory hormones and are present throughout the nervous and endocrine/hormonal systems. As neuroendocrine cells are distributed widely throughout the body, tumours of these cells can occur at many sites.
Examples of neuroendocrine tumours are:

• Carcinoid tumour;
• Pancreatic endocrine tumour;
• Gastrinoma;
• Insulinoma;
• Glucagonoma;
• VIPoma (vasoactive intestinal polypeptide tumour);
• Paraganglioma;
• Pheochromocytoma;
• Medullary thyroid carcinoma;
• Poorly differentiated small cell neuroendocrine carcinoma.

Statistics

Neuroendocrine tumours are generally rare. The incidence of pancreatic endocrine tumour is 0.1-1 per million per year. Glucagonomas are among the rarest of the NETs.

Risk Factors

The exact cause is unknown. Neuroendocrine tumours can arise spontaneously in a random fashion or as a result of genetic changes. Neuroendocrine tumours may associated with the following conditions inherited genetically:

• Multiple endocrine neoplasia (MEN) types 1 and 2;
• von Hippel-Lindau (VHL) disease;
• von Recklinghausens neurofibromatosis (NF);
• Tuberculous sclerosis (TSC).

Progression

Neuroendocrine tumours are rare cancers that are often misdiagnosed. Because symptoms vary widely depending on where the cancer happens, a diagnosis is frequently made only after the cancer has spread/metastasised to other parts of the body. Most neuroendocrine tumours are malignant, except insulinoma. They commonly spread to the lymph nodes and the liver. Some other uncommon sites of distant spread include the bone, lung, brain and other organs. Despite the ability to metastasise/spread, most malignant neuroendocrine tumours are slow-growing. An exception is the poorly differentiated small cell neuroendocrine carcinoma, which is highly malignant, fast-growing, but rare.
Depending on whether the neuroendocrine tumours lead to a specific clinical syndrome, they are termed “functionally active” and “functionally inactive”. Functionally active NETs produce clinical symptoms because of excessive hormone release from the tumour cell. Examples of NETs that may be functionally active are insulinoma, gastrinoma, VIPoma, glucogonoma (producing the glucagonoma syndrome), carcinoid tumour (producing the carcinoid syndrome).

Symptoms

NETs can be termed functionally active if they produce excessive hormones and lead to a specific clinical syndrome; and functionally inactive if they do not. Insulinoma, gastrinoma, VIPoma, glucagonoma and carcinoid tumour can be functionally active and give rise to various symptoms. Some of the clinical features produced by different neuroendocrine tumours include:

• Insulinoma: Symptoms of low blood sugar (intermittent confusion, sweating, weakness, nausea);
• Glucagonoma: Redness of the skin (necrotising migratory erythema), excessive weight loss and wasting, diabetes;
• VIPoma: Watery diarrhoea, disturbances of water balance;
• Gastrinoma: Excessive secretion of acid, peptic ulcer disease, gastro-oesophageal reflux disease, diarrhoea;
• Somatostatinoma: Diabetes, diarrhoea, gallstones.

On the other hand, functionally inactive neuroendocrine tumours, because of the lack of clinical symptoms, are usually diagnosed the following ways:

• By chance during routine ultrasound testing performed for other reasons (e.g. investigation of unexplained complaints of the upper abdomen);
• Jaundice (yellow discolouration of the skin and the eyes), in the case of large tumours at the head of the pancreas;
• Repeated abdominal cramping, in the case of apparent blockage (pseudo-obstruction) of the bowel by a functionally inactive neuroendocrine tumour in the small bowel (lower jejunum and ileum);
• Symptoms produced by the tumour (e.g. bleeding from the digestive tract).

Clinical Examination

Apart from taking a thorough history, a general physical examination will also be conducted by the doctor. The focus of the examination is largely dependent upon the nature of the history and the site of tumour suspected, for example the bowels, pancreas, stomach, adrenal glands (hormonal glands above the kidneys). The lymph nodes around the affected region and the liver will be felt for abnormalities from distant spread.

How is it Diagnosed

The usual basic tests will be done, including those to look at the blood and other blood components. Other general tests will determine the function of the liver and kidney.

Prognosis

Prognosis is different for different types of neuroendocrine tumour. For example:

• For insulinoma, long term survival following surgical removal in this patient population exceeds 90%;
• For carcinoid tumour, the survival rate at 5 years following diagnosis (5-year survival rate) for all carcinoid tumours, regardless of the site of tumour, is 67%.

Grading of the tumour based on findings under the microscope is difficult for neuroendocrine tumours. Recent research showed that in malignant neuroendocrine tumours, a few factors confer poor survival:

• A high expression of a protein called the Ki 67 protein;
• The presence of aneuploidy (abnormal amount of genetic material).

Treatment

The aim of treatment is to control tumour growth and the symptoms caused by hormone release.
Surgery

• Surgical removal is always attempted for benign tumours;
• In more extensive diseases, surgery is also considered to reduce the bulk of tumour.

Medical treatment

• Somatostatin analog: Mimics the hormone somatostatin, and is the drug of first choice to control symptoms. Octreotide and lanreotide is efficient in the control of watery diarrhoea in VIPoma, skin reddening in glucanogoma syndrome, and flushing & diarrhoea in carcinoid syndrome. Somatostatin analog also has effect on tumour growth control.
• Alfa-interferon: Since its use in 1982, alfa-interferon has been shown to be comparable to long-acting somatostain analog in the control of hormone release and tumour growth.
• Proton-pump inhibitors: At higher doses, this group of drugs can control excessive secretion of acid from the stomach in the case of gastrinoma.
• Chemotherapy: Neuroendocrine tumours in the pancreas respond well to chemotherapy. Tumours e.g. carcinoid tumour generally do not show good response to chemotherapy.

Other
Other treatment options include nutritional modification, radiofrequency ablation (the use of electrodes to heat and destroy abnormal tissue), cryoablation (the use of extreme cold to freeze abnormal tissue), chemoembolisation (blocking the blood supply to the tumour).

References

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