Biogenic amines as neuroendocrine tumor markers: limitations and future perspectives

Biogenic amines and their metabolites are central biochemical markers in the diagnosis and management of catecholamine-producing neuroendocrine tumors, including pheochromocytoma, paraganglioma, and neuroblastoma. Despite decades of clinical use, their wider implementation remains limited by substantial physiological variability, pre-analytical influences, and methodological heterogeneity across laboratories. The transition from colorimetric and immunoassay-based techniques to liquid chromatography-tandem mass spectrometry has markedly improved analytical sensitivity and specificity. The multiplexing capacity of modern mass spectrometric platforms has enabled comprehensive quantification of biogenic amine profiles, thereby increasing diagnostic sensitivity in tumor subtypes in which individual biomarkers exhibit limited performance. Increasing attention has been given to dopamine derived metabolites, especially 3-methoxytyramine, which is associated with MYCN-related tumor biology and unfavorable clinical outcomes in neuroblastoma and selected paraganglioma subtypes. However, the analytical complexity of mass spectrometric approaches, together with the absence of full metrological traceability, continues to limit inter-laboratory comparability. In this review, we critically evaluate the analytical evolution of biogenic amine testing, the principal pre-analytical and methodological determinants that influence the interpretation of results, and current efforts to improve harmonization. Particular emphasis is placed on the potential of biogenic amines as prognostic biomarkers and on the need to integrate expanded biogenic amine profiling into clinically robust, comparable diagnostic approaches that may advance precision oncology.