Catecholamines and Metanephrines: Quantification in the Diagnosis of Pheochromocytoma and Paraganglioma, Considerations and Critical Issues

Pheochromocytoma (PhC) and Paraganglioma (PG) are rare neuroendocrine tumors characterized by uncontrolled catecholamine secretion. Although rare, much attention is still devoted to identifying a unique biochemical signature of these diseases to reduce false positives, thus improving patient outcomes, and customizing clinical laboratory practices to available resources and specific diagnostic needs. Emerging knowledge into catecholamine metabolism has greatly improved diagnostic strategies, with current international guidelines recognizing plasma free or urinary fractionated metanephrine measurements as the recommended first-line biochemical tests. This narrative review highlights the clinical utility of measuring plasma free metanephrines compared to urinary catecholamines in the diagnosis of these conditions. Plasma free metanephrines offer superior sensitivity and specificity compared to catecholamines due to their continuous secretion, which is independent from tumor size and catecholamine fluctuations. This review also addresses preanalytical and methodological challenges, emphasizing patient preparation, sample stability and advanced analytical techniques currently available. Methodologies such as LC-MS/MS have demonstrated improved diagnostic accuracy compared to traditional immunoassays, offering enhanced analytical performance in terms of sensitivity, specificity, and reduced susceptibility to interferences.