True Chromogranin A concentrations in plasma from patients with small intestinal neuroendocrine tumours

Abstract

Objective: The incidence of enteropancreatic neuroendocrine tumours (NET) is increasing. Chromogranin A (CgA) in plasma is a marker in patients suspected of NET tumours. CgA, however, is a precursor protein subjected to cellular processing that challenges quantitation and hence the use of CgA in diagnostics.

Materials and methods: CgA concentrations in plasma sampled from 130 well-characterized patients with small intestinal NETs and from 30 healthy subjects were measured with eight commercial CgA kits, an in-house radioimmunoassay (RIA) and a processing-independent assay (PIA). For the evaluation of diagnostic accuracy, we performed regression analyses and plotted receiver-operating characteristic curves (ROC). The specificity was further assessed by size chromatography.

Results: Five commercial assays (Thermo-Fisher, DRG Diagnostics, Eurodiagnostica (RIA and ELISA), and Phoenix), displayed a diagnostic accuracy with area under the curve (AUC) values >0.90, whereas three immunoassays (Yanaihara, CisBio RIA, and CisBio ELISA) discriminated poorly between disease stages (AUC: 0.60–0.78). Compared with the in-house assays, however, even the most accurate commercial immunoassay still missed patients with metastatic disease. Chromatography showed non-uniform patterns of large and small CgA fragments in plasma.

Conclusion: Available commercial immunoassays measure CgA in plasma with gross variability. Three commercial CgA immunoassays discriminate so poorly between health and disease that they should not be used. The highest diagnostic accuracy was obtained with processing-independent measurement of total CgA concentrations in plasma.

Keywords:

• Chromogranin A
• diagnostic accuracy
• immunoassays
• neuroendocrine tumours
• small intestine processing-independent analysis (PIA)

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Acknowledgements

The expert technical assistance of Jane Lancaster and the expert secretarial assistance of Connie Bundgaard, Department of Clinical Biochemistry, Rigshospitalet, is gratefully acknowledged. We also acknowledge the statistical assistance from Bent Kristensen, Department of Clinical Physiology and Nuclear Medicine, Herlev Hospital.

Authors contributions

Study concept and design: LMH, UK, JFR; acquisition of data: KB, LMH, UK, JFR; analysis and interpretation of data: KB, LMH, JPG, JFR; drafting of the manuscript: KB, JPG, JFR; critical revision of the manuscript: JPG, LMH, UK, JFR; statistics: KB, BK; obtained funding: LMH, JPG, JFR.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work is funded by the Danish State Biotechnology Center for Cellular Communication. The funding organization played no role in the design of the study, choice of enrolled patients, review and interpretation of data, preparation of final approval of the manuscript.