Plasma tryptophan pathway metabolites quantified by liquid chromatography‐tandem mass spectrometry as biomarkers in neuroendocrine tumor patients

Abstract

AbstractA good and accessible biomarker is of great clinical value in neuroendocrine tumor (NET) patients, especially considering its frequently indolent nature and long‐term follow‐up. Plasma chromogranin A (CgA) and 5‐hydroxyindoleacetic acid (5‐HIAA) are currently used as biomarkers in NET, but their sensitivity and specificity are restricted. 5‐HIAA is the main metabolite of serotonin, an important neurotransmitter of the tryptophan pathway. The aim of this study is to estabish a sensitive and accurate method for the quantification of tryptophan pathway metabolites in plasma. We further aimed to evaluate its utility as a clinical tool in NET disease. We obtained plasma samples from NET patients and healthy controls recruited from the University Hospital of North Norway, Tromsø. Samples were analyzed by liquid chromatography‐tandem mass spectrometry (LC–MS/MS), and eight metabolites of the tryptophan pathway were quantified. We included 130 NET patients (72/130 small intestinal [SI] NET, 35/130 pancreatic NET, 23/130 other origin) and 20 healthy controls. In the SI‐NET group, 26/72 patients presented with symptoms of carcinoid syndrome (CS). We found that combining tryptophan metabolites into a serotonin/kynurenine pathway ratio improved diagnostic sensitivity (92.3%) and specificity (100%) in detecting CS patients from healthy controls compared with plasma 5‐HIAA alone (sensitivity 84.6%/specificity 100%). Further, a clinical marker based on the combination of plasma serotonin, 5‐HIAA, and 5OH‐tryptophan, increased diagnostic capacity identifying NET patients with metastasized disease from healthy controls compared with singular plasma 5‐HIAA, serotonin, or CgA. In addition, this marker was positive in 61% of curatively operated SI‐NET patients compared with only 10% of healthy controls (p < .001). Our results indicate that simultaneous quantification of several tryptophan metabolites in plasma, using LC–MS/MS, may represent a clinically useful diagnostic tool in NET disease.