Tests
1st tests to order
plasma free metanephrines or 24-hour urine fractionated metanephrines and normetanephrines
Test
Measurement of plasma free metanephrines, or 24-hour urine fractionated metanephrines and normetanephrines, is recommended in patients with suspected pheochromocytoma.[28][48]
Blood sampling should be performed in the supine position.[49]
When measuring 24-hour urinary excretion, creatinine is measured to ensure the adequacy of the collection.
Some drugs may interfere with testing results (e.g., acetaminophen, buspirone, cocaine, labetalol, levodopa, methyldopa, monoamine oxidase inhibitors [MAOIs], phenoxybenzamine, sotalol, sulfasalazine, sympathomimetics, tricyclic antidepressants); review patient drug history accordingly.[48]
Result
elevations 3 times above the upper limit of normal are diagnostic
genetic testing
Test
All patients with pheochromocytomas should undergo genetic testing to identify potential hereditary tumor disorders that would necessitate more detailed evaluation and follow-up.[1][28][48][49][57] Patient engagement in a shared decision-making process is essential.[48]
Genetic testing may be guided by features such as a positive family history (premised upon pedigree or identification of a PPGL-susceptibility gene mutation); syndromic features; multifocal, bilateral, or metastatic disease.[3]
Result
may reveal familial disorders responsible for pheochromocytoma such as Von Hippel-Lindau syndrome (VHL), multiple endocrine neoplasia type 2 (MEN2), or neurofibromatosis type 1 (NF1); other described gene mutations include SDHB, SDH complex assembly factor 2 (SDHAF2), transmembrane protein 127 (TMEM 127), SDH subunit A, MYC-associated factor X (MAX), and hypoxia-inducible factor 2-alpha (HIF2A)
Investigations to avoid
Tests to consider
CBC
Test
Erythrocytosis is a rare finding, secondary to overproduction of erythropoietin.[59]
Result
may reveal erythrocytosis
serum calcium
Test
Hypercalcemia may be seen in patients with multiple endocrine neoplasia 2 (MEN2) who have concomitant primary hyperparathyroidism.
Result
may reveal hypercalcemia
serum potassium
Test
Hypokalemia can be seen in the setting of high catecholamines.
Result
may reveal hypokalemia
chromogranin A
Test
Chromogranin A may be elevated in patients with a neuroendocrine tumor.
Reported sensitivity of 83% and specificity of 96% for identifying a pheochromocytoma.[60]
Chromogranin A plus urinary fractionated metanephrines has been suggested as a follow-up test for elevations of plasma metanephrines.[53]
Chromogranin A can be used as a screening tool to detect recurrence, especially in patients with normal preoperative metanephrine and normetanephrine levels.[57]
Result
elevated in patients with pheochromocytomas and multiple other neuroendocrine tumors
clonidine suppression test
Test
Discriminates patients with mildly elevated test results for plasma normetanephrine (attributable to increased sympathetic activity) from those with elevated test results due to a pheochromocytoma or paraganglioma.[49][52]
Used when potential for false-positive urine or serum studies (metanephrines/ normetanephrines) is high (e.g., patients with decreased renal excretory function, in acute alcohol withdrawal, or if the patient is taking hydralazine or minoxidil).
Plasma metanephrine and normetanephrine levels are taken both before and after administration of clonidine.[52][61] Consult your local drug information source for guidance on dose.
Clonidine is a centrally acting alpha-2-adrenergic receptor agonist that suppresses the release of catecholamines from neurons; however, it does not affect catecholamine secretion from a pheochromocytoma.
Result
lack of suppression of catecholamines
CT scan of the abdomen and pelvis
Test
Anatomic imaging (with CT, MRI, or both) is critical for surgical planning and should be performed for every patient.[26]
CT imaging is preferred.[48]
CT can detect adrenal pheochromocytomas as small as 0.5 cm and extra-adrenal disease >1 cm in diameter. [Figure caption and citation for the preceding image starts]: Abdominal CT scan with mass in the left adrenal gland, compatible with a pheochromocytomaAlface MM et al. BMJ Case Rep. 2015 Aug 4;2015:bcr2015211184; used with permission [Citation ends].
Localization studies should only be undertaken after a biochemical abnormality is demonstrated.
Result
inhomogeneous masses, often with a central area of low attenuation that represents hemorrhage or necrosis; the attenuation values are greater than 10 HU on unenhanced images
MRI of the abdomen and pelvis
Test
Anatomic imaging (with CT, MRI, or both) is critical for surgical planning and should be performed for every patient.[26]
MRI is an option for patients in whom radiation exposure should be limited or is contraindicated (e.g., children, pregnant or lactating women).[48]
MRI may be considered in patients with suspected metastatic pheochromocytoma or paraganglioma; it can detect blood vessel invasion and liver metastases with greater sensitivity than CT.[28]
Localization studies should only be undertaken after a biochemical abnormality is demonstrated.
Result
typically appear hyperintense to the liver on T2-weighted images because of their high water content
18F-fluorodeoxyglucose (18F-FDG) PET/CT or somatostatin receptor-targeted (SSTR) PET/CT with 68Ga-DOTATATE tracer
Test
Anatomic imaging should be complemented by functional imaging unless risk of tumor metastases or multifocal disease is low (i.e., those without previous pheochromocytoma or paraganglioma [PPGL] and hereditary syndrome, with an adrenergic biochemical phenotype and a single small adrenal pheochromocytoma [<5 cm]).[54]
Functional imaging can improve detection when anatomic localization is inconclusive, identify additional lesions in the setting of hereditary disease, and evaluate for metastatic disease.[55] The North American Neuroendocrine Tumor Society recommends SSTR PET/CT as first-line functional imaging when metastatic PPGL is suspected.[28]
18F-FDG PET/CT, and SSTR PET/CT with 68Ga-DOTATATE tracer (also known as PET/CT Ga-68 DOTATATEe scan), are more sensitive than I-123 metaiodobenzylguanidine (MIBG) scintigraphy in the setting of metastatic and multifocal pheochromocytoma.[28][48] SSTR PET/CT with 68Ga DOTATATE is highly sensitive, and often the preferred imaging modality for the detection and localization of pheochromocytoma in patients with SDHB-associated metastatic disease.[56]
Result
uptake of 18F-FDG is high in catecholamine-producing tissues on 18F-FDG PET/CT; uptake of 68Ga-DOTATATE is high in tissues expressing somatostatin receptors (e.g., paraganglioma) on SSTR PET/CT with 68Ga-DOTATATE tracer
I-123 metaiodobenzylguanidine (MIBG) scintigraphy
Test
Anatomic imaging should be complemented by functional imaging unless risk of tumor metastases or multifocal disease is low (i.e., those without previous pheochromocytoma or paraganglioma [PPGL] and hereditary syndrome, with an adrenergic biochemical phenotype and a single small adrenal pheochromocytoma [<5 cm]).[54]
Functional imaging can improve detection when anatomic localization is inconclusive, identify additional lesions in the setting of hereditary disease, and evaluate for metastatic disease.[55]
An I-123 MIBG scan is required if treatment with I-131 MIBG is being considered (e.g., patients with inoperable PPGL).[48][54]
I-123 MIBG scintigraphy is not recommended as a first-choice functional imaging study.[54][Figure caption and citation for the preceding image starts]: Metaiodobenzylguanidine (MIBG) scintigraphy identified hyperfixation in the left adrenal gland compatible with pheochromocytomaAlface MM et al. BMJ Case Rep. 2015 Aug 4;2015:bcr2015211184; used with permission [Citation ends].
Result
I-123 MIBG uptake intensity is high in catecholamine-producing tissues
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