Pheochromocytoma and Paraganglioma

Pheochromocytomas and paragangliomas are differentiated based on anatomical location.

Pheochromocytomas are neuroendocrine tumors that arise from the adrenal medulla.

Paragangliomas are neuroendocrine tumors that arise from extraadrenal sympathetic or parasympathetic paraganglia. Therefore paragangliomas can be found anywhere from the base of the skull to the pelvis.

Beyond the anatomical differences described earlier, pheochromocytoma and paraganglioma can exhibit biochemical differences.

Catecholamines are synthesized from a tyrosine substrate, which is ultimately transformed to produce dopamine, norepinephrine, and epinephrine.

Catecholamines typically circulate in low concentrations and have pulsatile and variable levels and short half-lives.

Catecholamines are further metabolized to inactive metabolites that have long and stable circulating half-lives. These metabolites are termed “metanephrines.” Norepinephrine is metabolized to normetanephrine, and epinephrine is metabolized to metanephrine. Together, these two metabolites are referred to as metanephrines. When ordering testing for metanephrines, the results appear as fractionated concentrations of normetanephrine and metanephrine. This terminology can be confusing as the singular and plural distinctions impart different meanings.

Dopamine is metabolized to the inactive metabolite termed “methoxytyramine”; however, the use of this metabolite is not common in clinical care, and this measurement is not widely commercially available.

The adrenal medulla expresses the enzymatic machinery to synthesize all the catecholamines. Therefore pheochromocytomas can exhibit a biochemical phenotype that includes elevated normetanephrine and/or elevated metanephrine (i.e., a pheochromocytoma can secrete norepinephrine and/or epinephrine).

In contrast, paragangliomas do not express the enzyme that converts norepinephrine to epinephrine and, therefore, do not secrete epinephrine (i.e., paragangliomas can secrete dopamine and/or norepinephrine).

Therefore, in practice, elevated normetanephrine levels could signify a pheochromocytoma or a paraganglioma, whereas elevated metanephrine levels could indicate a pheochromocytoma but not a paraganglioma.

Finally, it is worth remembering that pheochromocytomas and paragangliomas can be nonfunctional (i.e., neuroendocrine tumors that do not secrete catecholamines or metanephrines).

We now understand that 35% to 40% of all pheochromocytoma and paraganglioma are attributed to an inheritable (i.e., germline) pathogenic genetic mutation.

More than a dozen genetic mutations have been associated with pheochromocytoma-paraganglioma syndromes. Beyond developing these neuroendocrine tumors, some genetic syndromes predispose to developing other tumors and cancers as well.

For this reason, it is recommended that all patients with pheochromocytoma and paraganglioma be advised to consider genetic testing. The discovery of a genetic mutation often dictates a tumor surveillance program that involves imaging.

The following are genes associated with pheochromocytoma-paraganglioma syndromes:

• VHL (von-Hippel Lindau syndrome)

• RET (multiple endocrine neoplasia type 2)

• NF1 (neurofibromatosis type 1)

• SDHA (succinate dehydrogenase subunit A)

• SDHB (succinate dehydrogenase subunit B)

• SDHC (succinate dehydrogenase subunit C)

• SDHD (succinate dehydrogenase subunit D)

• SDHAF2 (succinate dehydrogenase subunit AF2)

• TMEM127 (transmembrane protein 127)

• MAX (myc-associated factor X)

• FH (fumarate hydratase)

• EPAS1 (hypoxia inducible factor 2a)

It is important to note that the majority of patients with a germline mutation, or hereditary pheochromocytoma-paraganglioma syndrome, do not display specific phenotypic features to help guide genetic testing. Therefore unless there are obvious phenotypic features indicative of a specific genetic syndrome (see Table), genetic testing should be conducted using a comprehensive and unbiased approach (i.e., gene panels).

For patients who are found to have a pathogenic germline mutation, screening of family members should be recommended. In addition, an imaging and biochemical surveillance program should be recommended to monitor for pheochromocytoma, paraganglioma, and other related tumors.

Patients should be managed by a multidisciplinary team with expertise in genetic testing and imaging surveillance protocols.