Clinical review 164: The laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience.

Abstract

P a catecholamine-producing tumor arising in the adrenal medulla, has an estimated incidence of two to eight cases per million persons annually (1, 2). Its clinical hallmark is sustained or intermittent hypertension often associated with paroxysmal symptoms (3). Pheochromocytoma should also be considered if a patient has labile hypertension, hypertension resistant to antihypertensive therapy, or paroxysmal symptoms (“spells”) (3, 4). Correct diagnosis is important because resection of the tumor dramatically reverses the clinical symptoms and may cure the hypertension (5). A missed or delayed diagnosis may cause considerable morbidity and mortality (5, 6). Clinically significant pheochromocytoma was first recognized in 1926 when Cesar Roux in Switzerland and Charles H. Mayo in the United States successfully removed pheochromocytomas to cure the catecholamine-associated symptom complex (7, 8). A biochemical assessment of catecholamine hypersecretion was not possible in 1926. Since then, the diagnostic approach has progressed from clinical impressions and exploratory laparotomies to histamine stimulation and phentolamine suppression tests in the 1940s, crude catecholamine measurements and iv urograms in the 1950s and 1960s, and refined measurements of catecholamine levels and computerized imaging in the 1970s and 1980s. Most laboratories now measure catecholamines by HPLC with electrochemical detection or gas chromatography and mass spectrometry. Catecholamines and their metabolites can be measured in the blood or urine. There are major regional, institutional, and international differences in the approach to the biochemical diagnosis of pheochromocytoma. For example, at Mayo Clinic, physicians have relied on the 24-h urinary excretion of catecholamines and total metanephrines for more than 2 decades (9, 10). If the baseline 24-h urinary studies are normal, the study is repeated when the patient is symptomatic (e.g. with a spell). From 1976–1993, Mayo Clinic clinicians performed histamine and glucagon stimulation tests (with measurement of blood pressure and plasma fractionated catecholamines) in 542 patients in whom pheochromocytoma was highly suspected despite normal 24-h urinary catecholamine or total metanephrine excretion; none of these patients had a positive stimulation test in this setting (11). Thus, we did not find the addition of histamine and glucagon stimulation tests helpful after 24-h urinary testing. The most recent addition to the biochemical testing armamentarium is fractionated plasma free metanephrines, a test proposed to be the superior to urinary testing by some investigators (12, 13). Herein, we focus on the biochemical tests used to diagnose sporadic adrenal pheochromocytoma. To provide perspective, two datasets from Mayo Clinic are summarized: 1) historical data before the use of fractionated free plasma metanephrines (1978–1996), and 2) current data obtained after the introduction of fractionated free plasma metanephrines (after 1998).