25th May 2025

Neuroendocrine Disorders

Neuroendocrine tumours (NETs) are rare. They can occur as secretory tumours which are more likely to present with symptoms. More commonly they present as non-functional tumours which do not produce hormones. Insulinoma and gastrinoma are the most common NETs. Investigations involve measuring serum hormone levels, imaging with CT/MRI/Endoscopic ultrasound (EUS) and somatostatin receptor scintigraphy. Medical management is typically with a somatostatin analogue such as octreotide or lanreotide. This works by inhibiting hormone secretion. Definitive management with surgery is preferred for tumours that have not metastasized.

Gastrinoma 

Gastrinomas are associated with gastrin secretion causing acid hypersecretion. This will present as dyspepsia and gastric/peptic ulcers and is also known as Zollinger-Ellison syndrome (ZES). Symptoms also include abdominal pain and diarrhoea. Tumours mainly occur in duodenum and less commonly the pancreas. They are slow growing but can metastasise to lymph nodes and liver. 

All patients with gastrinoma should be screened for MEN as about 25% of cases present as part of MEN.

Investigations

• Fasting serum gastrin level (raised)
• Gastric pH – <2
• Basal acid output or secretin test – measures gastric acid output via NG tube. Raised with gastrinoma

Note any gastrin/pH investigation will be affected by PPI so these must be held for 2 weeks prior to testing 

• Calcium, parathyroid and prolactin to rule out MEN

• CT/MRI/Endoscopic ultrasound – Tumours can be small and will not always be detectable on imaging

• Somatostatin receptor scintigraphy (SRSS)

Management

• PPI and H2 antagonists will often control symptoms
• Surgical resection if tumour identified
• Surgical exploration is advised in all sporadic (non MEN) cases if not identified on imaging +/- resection

Insulinoma

Insulinomas are insulin secreting tumours of the pancreas. This arises from APUD cells in the islets of Langerhans cells.  They typically present with hypoglycaemia from the endogenous production of insulin and these tend to occur during fasting or exercise. Around 20% of patients develop symptoms postprandially.  Whilst most tumours are benign, around 10% occur as part of MEN.

Differentiating between other causes of hypoglycaemia is important here. Differentials include exogenous insulin use and sulphonylurea use.

Investigations

Bloods in insulinoma should show: 

• Symptomatic hypoglycaemia <3.0mmol/L
• Insulin > 3.0uU/mL
• C-peptide > 0.6ng/mL
• Proinsulin ≥ 5 pmol/L

C-peptide is released when endogenous proinsulin is broken down into insulin. Therefore this will be raised only with endogenous insulin production and not with injectable/exogenous insulin use. Sulphonylureas (eg gliclazide) will cause the body to make insulin so this will also release C-peptide.

The below table summarises the interpretation of blood tests in determining the cause of hypoglycaemia. 

Table 1: interpreting blood test results in hypoglycaemia

To determine between insulinoma and sulphonylurea use (factitious hypoglycaemia) we can test for serum proinsulin levels (which would be significantly raised in insulinoma due to excess insulin production) or for serum or urine sulphonylurea.   

48-72 hour supervised fast: 

• in insulinoma this will invoke hypoglycaemia at which point the test stops
• Glucose, C-peptide and insulin levels should be sent off once hypoglycaemic

MRI/CT imaging

Endoscopic ultrasound if no visible lesion on imaging

GLP-1 receptor imaging (nuclear medicine scan specific for insulinoma)

Management

Management of hypoglycaemia: 

• Dietary, diazoxide – a drug which inhibits insulin secretion, octreotide to normalise blood glucose
• Definitive management:
  • Resectable disease: Laparoscopic (for small, single lesions), partial pancreatectomy, radical resection. Based on location and size of lesion.
  • Unresectable disease (if high risk, metastatic disease): radiofrequency ablation, embolization, intra-arterial chemotherapy – depending on patient factors and MDT decision

Carcinoid Syndrome

Carcinoid syndrome is a paraneoplastic syndrome caused by the release of neuroendocrine hormones including serotonin. It is more common with midgut NETs and in those with liver metastases. It causes flushing, wheeze, pellagra, abdominal pain and palpitations. It can be diagnosed by 24 hour urinary 5-HIAA. Treatment is by managing the underlying tumour.

Multiple neuroendocrine neoplasia (MEN)

MEN is an autosomal dominant disorder which is defined by multiple neuroendocrine tumours.  MEN is caused by the RET oncogene mutation. The most common tumours associated are listed below however any neuroendocrine tumour can present as part of the condition including the pancreas, duodenum, lung and thymus. Patients identified at high risk of MEN tumours due to family history should be offered annual biochemical and radiological screening under MDT review. Treatment consists of treating the individual tumours. MEN1 is caused by a MEN gene mutation whereas MEN2 is caused by RET oncogene mutation. MEN is diagnosed by genetic testing either through surveillance due to family screening or if it suspected when someone develops a MEN tumour, such as a parathyroid, pancreatic neuroendocrine tumour or pituitary gland tumour. These tumours would present as expected –for example, with hyperparathyroidism or as a functioning or non-functioning pituitary tumour. Investigations would include bloods for calcium and hormone levels and imaging such as CTCAP and MRI pancreas. 

MEN1: parathyroid adenoma (90%), pancreas (30-70%), pituitary (30-40%) 

MEN2A: medullary thyroid (90%), phaeochromocytoma (50%), parathyroid adenoma (20-30%) 

MEN2B: medullary thyroid (>90%), phaeochromocytoma (40-50%), mucosal neuromas, marfanoid features

Von-Hippel-Landau disease and neurofibromatosis also inherited disorders associated with the development of neuroendocrine tumours.

Von-Hippel-Landau: presents with haemangioblastomas in the CNS and retina, phaeochromocytoma, increased risk of renal cell carcinoma and liver and renal cysts. 

Neurofibromatosis 1 (NF1): presents in late childhood with characteristic café-au-lait spots, cutaneous neurofibromas, plexiform neurofibromas, phaeochromocytoma, as well as cardiovascular and neurological disorders. 

Neurofibromatosis 2 (NF2): significantly less common and presents in adulthood. It is characterised by bilateral vestibular neuromas/Schwannomas which can lead to deafness and hearing loss, as well as

Rare Functional Neuroendocrine tumours

Discussed below are some functional pancreatic neuroendocrine tumours. These can occur on their own or in around 10% as part of a familial endocrine tumour group like MEN or VHL. Therefore, family history is important here. Neuroendocrine tumours can also be non-functional, when they do not secrete an enzyme but can still be locally invasive and metastasise.

References

Rajesh V. Thakker, Paul J. Newey, Gerard V. Walls, John Bilezikian, Henning Dralle, Peter R. Ebeling, et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1), The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 9, 1 September 2012, Pages 2990–3011

Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M et al. Vienna Consensus Conference participants. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology. 2016;103(2):153-71. doi: 10.1159/000443171. Epub 2016 Jan 5. PMID: 26742109; PMCID: PMC4849884.

Metz DC. Diagnosis of the Zollinger–Ellison syndrome. Clin Gastroenterol Hepatol. 2012 Feb;10(2):126-30. doi: 10.1016/j.cgh.2011.07.012. Epub 2011 Jul 30. PMID: 21806955.

Zollinger-Ellison Syndrome. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/408

Non-diabetic hypoglycaemia. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/509