Endocrine Abstracts

Paragangliomas (PGLs) derive from either sympathetic tissue in adrenal and extra-adrenal locations, or from parasympathetic tissue of the head and neck. Adrenal PGLs are usually referred to as pheochromocytomas. Most patients with adrenal and extra-adrenal abdominal PGLs have increased plasma and urine concentrations of catecholamines (dopamine, norepinephrine and epinephrine). Typical symptoms and signs of catecholamine excess include headache, palpitations, diaphoresis, and hypertension. Although PGL is a rare cause of hypertension, the diagnosis is considered frequently by clinicians in patients with refractory hypertension or symptoms or signs of catecholamine excess.

In about 8–9% of patients with sporadic PGL and 21–31% with hereditary PGL plasma concentrations and urinary outputs of catecholamines are normal. Nevertheless, such patients invariably have elevated plasma concentrations of the metanephrines, normetanephrine and metanephrine. These O-methylated metabolites of norepinephrine and epinephrine are produced continuously within tumor cells and independently of catecholamine release, which can be variable or negligible, even in patients with large tumors. Exceptions where plasma metanephrines can be normal include patients with very small tumors (<1 cm) that do not synthesize and metabolize sufficient amounts of catecholamines to produce positive test results. Other rare exceptions include patients with PGLs that only produce dopamine and which may be detected by increases in plasma methoxytyramine, the O-methylated metabolite of dopamine. In contrast to PGLs derived from sympathetic tissue, the vast majority (95%) of head and neck PGLs do not produce significant amounts of (nor)epinephrine.

At least 30% of the PGLs are caused by germline mutations in ten identified tumor susceptibility genes viz., RET, NF1, VHL, succinate dehydrogenase subunits A, B, C, D and assembly factor 2 (SDHA/B/C/D/AF-2), TMEM127 and MAX. These genotypes correlate with distinct biochemical phenotypes characterized by differences in catecholamine metabolomic and secretory signatures.