The causes of most NETs are not fully understood, and there is currently no clear prevention strategy.
However, when there is a history of hereditary conditions the risk is greater, and genetic screening and regular reviews need to be in place to detect early asymptomatic cancer (refer to section 1.3).

The risk factors for developing NETs include (Cancer Centre 2021; Roswell Park 2021; Department of Health and Ageing 2013):

• hereditary conditions such as multiple endocrine neoplasia type 1 (MEN-1), multiple endocrine neoplasia type 2 (MEN-2), von Hippel-Lindau disease (VHL), phacomatoses (neurocutaneous syndromes)
• genetic disorders associated with multiple tumours – for example, tuberous sclerosis and neurofibromatosis
• conditions that affect stomach acid, such as pernicious anaemia and chronic atrophic gastritis
• age – although NETs can occur at any age, there are some age groups that specific NETs can occur in, such as appendiceal NETs in a younger age group.

Some people have hereditary conditions that may predispose them to forming a NET. These people should be surveilled for syndrome-specific diagnosis and monitored annually. Hereditary conditions include (Rogel Cancer Centre University of Michigan 2021):

• multiple endocrine neoplasia (MEN)
  • MEN-1 – at risk of developing pituitary adenomas (PitNETs), pancreatic neuroendocrine tumours (pNETs) and hyperparathyroidism
  • MEN type 2A (RET gene mutation) – at risk of developing medullary thyroid cancer, hyperparathyroidism and phaeochromocytoma, noting that some families will only express medullary thyroid cancer
  • MEN type 2B (also known as MEN-3) (RET) – at risk of developing medullary thyroid cancer at a very young age, pheochromocytoma and mucosal neuromas of the lips, tongue and eyelids
  • MEN type 4 (CDKN1B gene mutation) – at risk of developing pituitary tumours, pancreatic NETs and hyperparathyroidism
  • MEN type 5 (MAX) – at risk of developing phaeochromocytomas and pituitary NETs
• VHL– at risk of developing pheochromocytomas, central nervous system and retinal haemangioblastomas, inner ear tumours, kidney tumours and pancreatic NETs
• succinate dehydrogenase gene complex (SDHA/B/C/D) mutations / paraganglioma syndrome – increased risk of phaeochromocytomas, paragangliomas, stomach gastrointestinal stromal tumours, kidney cancers and PitNETs
• fumarate hydratase mutations, which cause hereditary leiomyomatosis and renal cell carcinoma syndrome characterised by renal carcinomas, benign smooth muscle tumours of the skin and uterus and, occasionally, phaeochromocytoma and paragangliomas
• TMEM127 mutations – increased risk of phaeochromocytomas, paragangliomas and renal cell cancers.

For more information visit:

• phaeochromocytoma/paraganglioma panel testing
• VHL disease risk management

Increased awareness among health professionals is paramount to enable early diagnosis. There is often a prolonged delay in diagnosis because features are non-specific. General practitioners should have a strong clinical suspicion of patients who present with a combination of symptoms, or persistent symptoms (see section 2.1 for symptoms).