Tumours derived from neuro-endocrine or chromaffin cells. These may occur in isolation or as part of MEN1 or neurofibromatosis. The diagnosis carcinoid syndrome refers to the association of diarrhoea and flushing associated with peptide secretion from these tumours.
If the diagnosis of MEN1 or neurofibromatosis is clinically likely, for example in the presence of skin changes or with hyperparathyroidism or pituitary disease, discuss genetic testing.
Baseline investigations - all patients
Anaemia is a non specific marker of malignancy and always requires further investigation. B12 deficiency suggests terminal ileal disease.
Hypokalaemic acidosis may occur with severe diarrhoea, for example due to VIPoma.
Hyponatraemia may occur with salt and water depletion.
Useful indicator of possible liver metastases.
Hypercalcaemia may occur with neuro-endocrine tumours, with metastic disease or with associated hyperparathyroidism in MEN1.
These are useful baseline measurements. Hypoglycaemia raises the possibility of an occult insulinoma, and may occur with glucocorticoid deficiency or metastatic disease.
Many pancreatic neuro-endocrine tumours lead to glucose intolerance, for example glucagonomas.
Gut hormones should be documented as soon as a neuro-endocrine tumour is suspected and may provide a useful indicator of disease burden following treatment.
This needs to be performed after a 12 hour fast with a concurrent sample for urea, electrolytes and calcium. This test should include chromogranin A and B, vasoactive intestinal peptide VIP, somatostatin, glucagon, gastrin, pancreatic polypeptide PP and neurotensin.
Proton pump inhibitors need to be stopped for at least two weeks, and H2 (histamine 2 receptor) antagonists stopped for at least three days prior to testing where possible, and a complete medication list is required for interpretation of results.
Urinary 5-hydroxyindole acetic acid is a metabolite of serotonin produced by carcinoid tumours. It is detectable in the urine in metastatic disease.
False positives may occur with certain foods, for example bananas, avocado, aubergine, nuts and tomatoes, as well as various cough and cold preparations.
When a NET is confirmed, basal pituitary function should be documented due to the association with pituitary tumours in MEN1. Further tests should be considered if indicated. ACTH and other pituitary and hypothalamic peptides may also be secreted by NETs.
Testing should include prolactin, 9am cortisol, thyroid stimulating hormone, free thyroxine, growth hormone, insulin like growth factor-I, luteinising hormone, follicle stimulating hormone, sex hormone binding globulin and estrodiol/testosterone.
Further investigations - selected cases only
Full investigation for possible insulinoma requires a supervised fast.
This should be performed at baseline as a screen for malignant disease, for thymic or bronchial lesions, for cardiac complications and prior to considering surgery.
ECG should be performed in all patients at baseline to document and confirm any arrhythmias or other changes.
This should be performed at baseline and repeated if clinically indicated or on an annual basis in a patient with a functioning NET or carcinoid syndrome.
CT or MRI scanning of the abdomen, chest and pelvis should be performed in all cases of confirmed NET to locate the primary, and to stage metastatic disease. Fifty percent of NETs arise within the small bowel or pancreas.
Ultrasound imaging will often provide further useful anatomical information for example if cysts are suspected.
Endoscopic ultrasound can also identify tiny pancreatic lesions and provide further detailed anatomical information about the pancreas.
Barium examination may be useful in possible sub acute bowel obstruction, or to aid localisation of the primary tumour.
If the patient complains of severe upper gastrointestinal symptoms suggestive of peptic ulcer disease, or has other warning features, for example anaemia or weight loss, direct visualisation of the upper gastrointestinal tract is essential.
OGD with follow through or push enteroscopy may also be performed to locate and allow biopsy of small bowel lesions.
Selective angiography, with calcium infusion to stimulate peptide secretion during sampling, may be performed to aid precise localisation of biochemically proven functioning lesions and to define anatomy prior to pancreatic surgery.
This is usually performed to aid localisation of NETs, and to detect metastatic disease prior to surgery.
This may also be performed to aid localisation of NETs, particularly if they are not obvious on MIBG scanning.
Parathyroid hormone should always be tested in the patient with hypercalcaemia.
If elevated, this implies parathyroid disease and MEN1 which should be investigated and treated appropriately, rather than tumour associated hypercalcaemia.
Useful to document vitamin D levels to aid interpretation of serum calcium and PTH levels.
This should be performed in all cases of MEN1 at diagnosis, or if pituitary disease is suspected.