Approach

History

A pheochromocytoma should be suspected in any patient who presents with the classic triad of symptoms:[1][2]​​[3][43]

  • Palpitations

  • Headaches

  • Diaphoresis.

Episodic spells of the symptoms are characteristic; they can vary in duration from seconds to hours and typically get worse with time as the tumor enlarges.

Other suggestive features:

  • Resistant intractable hypertension

  • Young age at the onset of hypertension.

Inquiring about the family history is vital. Up to 40% of pheochromocytoma and paraganglioma (PPGL) cases are a manifestation of a hereditary syndrome (e.g., multiple endocrine neoplasia [MEN] syndrome type 2A and B; Von Hippel-Lindau [VHL] disease; neurofibromatosis type 1 [NF1]).[1][2][3] Germline mutations in the succinate dehydrogenase [SDH] subunit B, C, and D genes, or a personal history of a pheochromocytoma, increase risk.[35][36] 

Clinical presentation of pheochromocytoma can vary widely and 10% to 15% of cases can be completely asymptomatic with the tumor discovered incidentally during abdominal investigation for other reasons.[44] Approximately 3% to 7% of incidentally discovered adrenal masses are diagnosed as pheochromocytoma.[44] It is recommended that all patients with such masses should undergo biochemical evaluation.[45][46]

Physical exam findings

Hypertension is the principal sign on examination.[47] Patients often present with accelerated hypertension or hypertension refractory to multiple drug regimens. In about 48% of cases the hypertension is paroxysmal or labile in nature.[47] Pheochromocytomas may present with life-threatening acute hypertensive emergencies (e.g., encephalopathy), as well as clinical consequences of long-lasting hypertension (e.g., hypertensive retinopathy, proteinuria, cardiomyopathies, or arrhythmias).[47] A hypertensive crisis can be triggered by medications, intravenous contrast, surgery, or even exercise. Postural hypotension may be a feature due to volume contraction. Other signs associated with pheochromocytomas include abdominal masses, tachycardia, pallor, or tremors.[1][3]

Laboratory evaluation

All patients with palpitations, headaches, and diaphoresis should be investigated, whether they have hypertension or not.[27]

Investigations should be carried out in any patient with hereditary risk that predisposes to pheochromocytoma development, such as MEN2.[27]

Biochemical tests

Measurement of plasma free metanephrines, or 24-hour urine fractionated metanephrines and normetanephrines, is recommended in patients with suspected pheochromocytoma.[2][27][43]​​ Elevations 3 times above the upper limit of normal are diagnostic.[43] 

Blood sampling should be performed in the supine position.[2][26]​​​ 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 medications accordingly.[2][43]​​​ 

Note that urine or plasma catecholamines are no longer routinely recommended for the evaluation of pheochromocytoma.[27][43][48][49]​​​​​

A clonidine suppression test can be used to discriminate patients with mildly elevated test results for plasma normetanephrine (attributable to increased sympathetic activity) from those with elevated test results due to a PPGL.[2] 

Chromogranin A may be elevated in patients with a neuroendocrine tumor; chromogranin A plus urinary fractionated metanephrines have been suggested as follow-up tests for elevations of plasma metanephrines.[50]

Imaging studies

Localization studies should only be undertaken after a biochemical abnormality is demonstrated.

CT imaging is recommended given its excellent spatial resolution in the abdomen; MRI is an option for patients in whom CT imaging is contraindicated.[2][16]

Multiphasic abdomen/pelvis CT or MRI, 18F-fluoro-2 deoxy-D-glucose (18F-FDG) PET/CT, or I-123 metaiodobenzylguanidine (MIBG) scintigraphy are performed, as appropriate, in the presence of metastatic or multifocal disease.[43] 18F-FDG PET/CT is preferred to MIBG scintigraphy in this scenario.[2][43] [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].com.bmj.content.model.Caption@8189c43[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].com.bmj.content.model.Caption@2bde6876

Genetic testing

All patients with pheochromocytomas should undergo genetic testing to identify potential hereditary tumor disorders that would necessitate more detailed evaluation and follow-up.[1][2][43]​ Patient engagement in a shared decision-making process is essential.[2][43]

Genetic testing may be considered in patients with pheochromocytoma with:[2]

  • Positive family history (premised upon pedigree or identification of a PPGL-susceptibility gene mutation)

  • Syndromic features

  • Multifocal, bilateral, or metastatic disease

Targeted germline mutation testing (e.g, multiple endocrine neoplasia type 2 [MEN2], Von Hippel-Lindau syndrome [VHL], and neurofibromatosis type 1 [NF1]) is recommended in patients with positive family history or syndromic presentation.[2]  Patients with metastatic disease should undergo testing for SDHB mutations.

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