Approach

History

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

  • 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. Approximately 35% to 40% of patients with pheochromocytoma or paraganglioma (together known as PPGL) have a germline mutation in one of the known PPGL susceptibility genes such as RET (associated with multiple endocrine neoplasia type 2) or VHL (associated with Von Hippel-Lindau syndrome).[1][3][4][5] Germline mutations in the SDH subunit B, C, and D genes, or a personal history of a pheochromocytoma, increase risk.[36][37]

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 drugs, 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 or not they have hypertension.[28]

Investigations should be carried out in any patient with hereditary risk that predisposes to pheochromocytoma development, such as MEN2.[28]

Biochemical tests

Measurement of plasma free metanephrines, or 24-hour urine fractionated metanephrines and normetanephrines, is recommended in patients with suspected pheochromocytoma.[28][48] Elevations 3 times above the upper limit of normal are diagnostic.[48]

Blood sampling should be performed in the supine position.[49] 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]

Note that urine or plasma catecholamines are no longer routinely recommended for the evaluation of pheochromocytoma.[28][48][50][51]

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 pheochromocytoma or paraganglioma.[49][52]

Chromogranin A (an acidic monomeric protein that is stored with and secreted with catecholamine) may be elevated in patients with a neuroendocrine tumor. Chromogranin A plus urinary fractionated metanephrines has been suggested as a follow-up test for elevations of plasma metanephrines.[53]

Imaging studies

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

Computed tomography (CT) imaging is preferred.[48] Magnetic resonance imaging (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 PPGL; it can detect blood vessel invasion and liver metastases with greater sensitivity than CT.[28]

Anatomic imaging should be complemented by functional imaging unless risk of tumor metastases or multifocal disease is low (i.e., those without previous PPGL and hereditary syndrome, with an adrenergic biochemical phenotype and a single small adrenal pheochromocytoma [<5 cm]).[54][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@4daaa908

Functional imaging

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 somatostatin receptor-targeted (SSTR) positron emission tomography (PET)/CT as first-line functional imaging when metastatic PPGL is suspected.[28]

18F-fluorodeoxyglucose (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]

An I-123 MIBG scan is required if treatment with I-131 MIBG is being considered (e.g., patients with inoperable PPGL).[48][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].com.bmj.content.model.Caption@2b5eec81

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][28][48][49][57] Patient engagement in a shared decision-making process is essential.[48]

Genetic testing may be guided by features such as:[3]

  • 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.[3]

Patients with metastatic disease should undergo testing for SDHB mutations.

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