Investigations
1st investigations to order
serum calcitonin (MEN2)
Test
Elevated levels suggest medullary thyroid cancer.
US guidelines recommend measuring serum calcitonin levels in symptomatic patients, those who are known MEN2 carriers, and/or those with suspicious biopsy results.[51]
In some European centres, measurement of serum calcitonin levels is recommended as part of routine thyroid nodule evaluation in case medullary thyroid cancer is missed on routine fine needle aspiration.[52]
Serum calcitonin levels are measured to assess disease status after surgery and are useful in follow-up and management. The calcitonin doubling time can provide useful prognostic information (doubling time >2 years better than doubling time <6 months).[53]
Result
raised
serum carcinoembryonic antigen (MEN2)
Test
Levels may be elevated in medullary thyroid cancer. This is not a specific marker of medullary thyroid cancer and can be elevated in a number of other conditions, including bowel cancer.
Can be used to screen for disease recurrence along with a calcitonin.
Useful to measure preoperatively.
Result
raised
plasma metanephrines (MEN2)
Test
Elevated levels suggest phaeochromocytoma.
An alternative screening tool for asymptomatic patients. It is more sensitive but less specific than urine metanephrine measurement.[54]
False-positive rates are higher, meaning positive tests should be confirmed with urine collections and imaging. Plasma and urine metanephrines can be falsely elevated by a large number of medications (including paracetamol).[54]
Result
raised
serum parathyroid hormone and calcium (MEN1/2)
Test
Elevated parathyroid hormone levels associated with elevated serum calcium levels suggest primary hyperparathyroidism due to parathyroid adenomas or parathyroid gland hyperplasia.
Primary hyperparathyroidism leads to above-normal elevation of serum calcium levels.
Vitamin D deficiency is the most common cause of elevated serum parathyroid hormone levels (secondary hyperparathyroidism). In vitamin D deficiency, ionised serum calcium is low to normal.
When serum calcium levels do not permit distinction between primary and secondary hyperparathyroidism, serum 25-OH vitamin D may be required, along with exclusion of familial hypocalciuric hypercalcaemia (FHH).
Result
raised
fasting serum gastrin (MEN1)
Test
Elevated up to 10 times the upper limit of normal if gastrinoma present.
Fasting gastrin levels are elevated in the presence of gastrinomas. However, they are also elevated by similar amounts with Helicobacter pylori infection and chronic proton-pump inhibitor use.[55]
Result
raised
serum chromogranin A (MEN1)
Test
Elevated levels suggest neuroendocrine tumours.
Yearly serum levels provide useful biochemical screening for patients with MEN1.
Result
raised
serum prolactin (MEN1)
Test
Elevated in the presence of prolactinoma, macroadenoma (due to pituitary stalk compression), and elevated in 15% to 20% of growth hormone-secreting adenomas.
Other non-malignant or non-neoplastic causes of elevated prolactin need to be ruled out (e.g., pregnancy, antipsychotic drugs, promotility drugs, and chest wall injuries).
Result
raised
insulin-like growth factor-1 (MEN1)
Test
Elevated levels suggest growth hormone-secreting adenomas.
Requires correction for age and sex.
Result
raised
24-hour urine metanephrines and catecholamines (MEN2)
Test
Elevated levels above twice the upper limit of normal suggest phaeochromocytoma.
All patients with MEN2 require annual screening for phaeochromocytoma and before thyroid surgery to prevent hypertensive emergency during anaesthesia.
Drugs such as beta-blockers may interfere with the metabolism of these hormones and lead to false results.[54]
Result
raised
24-hour urine calcium (MEN1/2)
Test
Elevated levels suggest primary hyperparathyroidism.
Low-to-normal levels indicate the presence of vitamin D deficiency. Low levels suggest familial hypocalciuric hypercalcaemia (FHH) or thiazide diuretic use.
Result
low, normal, or raised
thyroid biopsy (MEN2)
Test
Thyroid biopsy by fine needle aspiration (FNA) is recommended for thyroid nodules that have suspicious characteristics on ultrasound, including calcification, ill-defined borders, or increased vascularisation. FNA samples should be stained for calcitonin.
Result
atypical cells or medullary thyroid cancer
Investigations to consider
fasting serum glucose/insulin (MEN1)
Test
Insulinomas are suspected in patients with neuroglycopenic symptoms if insulin levels are not suppressed in the presence of symptomatic hypoglycaemia.
Supervised 72-hour fasting in controlled environments may be necessary to elicit symptoms and hypoglycaemia before diagnosis is possible.
Result
non-suppressed insulin levels when glucose level <2.5 mmol/L (<45 mg/dL) if insulinoma present
serum C peptide (MEN1)
Test
Elevated or normal with insulinoma; suppressed if exogenous insulin is being given.
Rules out factitious hypoglycaemia due to insulin self-injection, which can cause the same symptoms as insulinoma.
Result
elevated; normal or suppressed
calcium-stimulated gastrin (MEN1)
Test
Calcium stimulates tumour secretion of gastrin much more than normal tissue.
If gastrinoma is present, gastrin levels increase by >50% above 185 picomol/L (385 picogram/mL) after calcium infusions.[56]
Result
raised
serum proinsulin (MEN1)
Test
Elevated levels suggest neuroendocrine tumours.
Annual measurement provides useful biochemical screening for patients with MEN2.
Result
raised
serum pancreatic polypeptide (MEN1)
Test
Elevated levels suggest neuroendocrine tumours.
Annual measurement provides useful biochemical screening for patients with MEN1.
Result
raised
serum glucagon (MEN1)
Test
Elevated levels suggest neuroendocrine tumours.
Annual measurement provides useful biochemical screening for patients with MEN1.
Result
raised
T4 (free thyroxine) (MEN1)
Test
Reduced levels suggest central hypothyroidism from large pituitary tumours.
Elevated levels in the context of a normal/elevated thyroid-stimulating hormone (TSH) suggest TSH-producing tumours.
Disordered feedback between TSH and free T4 often suggests central axis problems. The relationship can be complicated because the pituitary can make a detectable but inactive TSH. Because of this, a low T4 with a normal TSH may be a central problem even though the pituitary hormone (TSH) seems normal.
Result
low or elevated
thyroid-stimulating hormone (TSH) (MEN1)
Test
Reduced or normal levels suggest central hypothyroidism from large pituitary tumours.
Elevated levels suggest thyroid-stimulating hormone (TSH)-producing tumours.
Disordered feedback between TSH and free thyroxine (T4) often suggests central axis problems. The relationship can be complicated because the pituitary can make a detectable but inactive TSH. Because of this, a low T4 with a normal TSH may be a central problem even though the pituitary hormone (TSH) seems normal.
Result
low, normal, or elevated
dexamethasone suppression test (MEN1/2)
Test
The overnight dexamethasone suppression test (dexamethasone 1 mg taken at 11 p.m. the previous night) can be used as an initial screening test, but if there is a high index of clinical suspicion a 2-day low-dose dexamethasone suppression test should be performed.
Failure to suppress serum cortisol to <50 nanomol/L (<1.8 micrograms/dL) is suggestive of Cushing's syndrome.
Screening tests may be falsely positive in several disorders including depression, alcohol abuse, anorexia nervosa, and severe obesity.
Abnormal results with one modality require confirmation with a second test modality.[57]
Result
failure to suppress serum cortisol to <50 nanomol/L (<1.8 micrograms/dL) is abnormal
urine sulphonylurea (MEN1/2)
Test
Present in urine if the patient is taking sulphonylurea medications.
Urine tests for sulphonylureas are needed to rule out factitious hypoglycaemia in patients with suspected insulinomas.
Result
present if patient on sulphonylureas
metaiodobenzylguanidine scintiscan (MIBG) (MEN2)
Test
Adrenal uptake suggests phaeochromocytoma.
Uptake in other locations suggests paraganglionoma or metastatic disease. Adrenal medullary imaging confirms the presence of phaeochromocytoma (biochemical markers are preferred to make the initial diagnosis).
Localisation and confirmation is helpful before surgery, especially in patients with multiple foci.
Result
adrenal uptake
18F-fluorodihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET)/CT abdomen and pelvis (MEN2)
Test
In one small study, 18F-DOPA PET and CT appeared to be better than either PET or CT alone at diagnosing and localising phaeochromocytomas.[46] 18F-DOPA PET is more sensitive and specific than metaiodobenzylguanidine (MIBG) scanning at detecting phaeochromocytoma in extra-adrenal and hereditary disease.[47]
Result
uptake of 18F-DOPA is high in catecholamine-producing tissues; mass seen on CT
octreotide scan (MEN1)
Test
Radiolabelled octreotide will bind to neuroendocrine tumours if they are present.
Can be used following the detection of biochemical neuroendocrine tumour markers to help localise tumours for surgery or to clarify the nature of tumours visualised on other imaging.
Very sensitive for islet cell tumours.
Not as sensitive for gastrinomas or insulinomas (often smaller and multiple).[45]
Result
uptake in neuroendocrine tumours
gallium-68 DOTATATE PET/CT abdomen and pelvis (MEN1 and 2)
Test
In one study gallium-68 DOTATATE PET/CT imaging has been shown to be the superior modality for identifying and mapping well-differentiated neuroendocrine tumours and outperforms indium octreotide scanning in patients with neuroendocrine tumours.[58]
Result
high affinity for neuroendocrine tumours
technetium 99 sestamibi scintiscan (MEN1/2)
Test
Increased uptake at the parathyroid gland (in delayed images after thyroid washout) suggests parathyroid adenoma.
These parathyroid gland scans are often negative in multiglandular hyperplasia but are part of standard initial workups for sporadic primary hyperparathyroidism.
MEN can be considered if there is multifocal uptake in patients with apparently sporadically occurring primary hyperparathyroidism.
Scanning is not used routinely for patients with known MEN who are going to surgery. This is because all glands will be visualised intraoperatively regardless of scan results. However, scans can be helpful before re-operation in these patients.[3]
Result
increased uptake in parathyroid adenoma
abdominal CT (MEN1/2)
Test
Pancreatic masses or adrenal masses with elevated Hounsfield units and delayed washout may be visualised.
The characteristic patterns of dye uptake and retention make adrenal protocol CT the preferred test for suspected phaeochromocytoma.
Imaging can be used at intervals to supplement biochemical screening for MEN1. Consensus guidelines suggest such imaging be performed annually for pancreatic masses and every 3 years for adrenal masses, although this may be mitigated by biochemical surveillance.[3]
Result
adrenal or pancreatic masses
abdominal MRI (MEN1/2)
Test
An alternative to CT for identification of abdominal masses.
High signal intensity on the T2-weighted imaging sequence is typical of phaeochromocytomas, although not always present.
Result
adrenal or pancreatic masses
chest CT or MRI (MEN1)
Test
Due to the increased risk of bronchial and mediastinal (including thymic) neuroendocrine tumours, current consensus guidelines recommend thoracic imaging every 1 to 2 years.[3]
Result
thymic or bronchopulmonary masses
pituitary MRI (MEN1)
Test
Best assessment of pituitary gland anatomy. Adenoma may be visualised on fine cuts of the pituitary.
Non-functioning and clinically irrelevant pituitary microadenomas are prevalent in the general population.
Biochemical studies are necessary to determine whether the adenoma is hormonally active.
Pituitary radiology should be carried out at baseline and then every 3 years, with annual biochemical screening according to consensus guidelines.[3]
Result
adenoma
endoscopic ultrasonography (MEN1)
Test
A sensitive tool for localisation of pancreatic lesions and some duodenal lesions.[48]
Result
pancreatic or duodenal masses
upper gastrointestinal endoscopy (MEN1)
Test
Endoscopy of patients with Zollinger-Ellison syndrome can help to detect the presence of gastrinomas; however, endoscopic ultrasound is generally the preferred investigation.
Result
may show findings consistent with a gastrinoma
Helicobacter pylori breath test, biopsy, or stool antigen test (MEN1/2)
Test
Patients with ulcers and resistant gastro-oesophageal reflux generally have H pylori testing with urea breath tests, biopsies, or stool antigen testing as part of their initial evaluation. H pylori infection is vastly more common than gastrinoma (unless patients are known to have MEN1), and should be ruled out before diagnosis is made.
Result
positive if H pylori present
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