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Diagnostic Accuracy of Chromogranin A and Calcitonin Precursors Measurements for the Discrimination of Ectopic ACTH Secretion from Cushing’s Disease

The Program in Reproductive and Adult Endocrinology (M.S.Z., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Veterans Affairs Medical Center and George Washington University (E.S.N., K.L.B.), Washington, DC 20422; Department of Diagnostic Radiology (N.J.P.), Warren O. Hatfield Clinical Research Center, National Institutes of Health, Bethesda, Maryland 20892; and Surgical Neurology Branch (E.H.O.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Lynnette Nieman, M.D., Building 10, CRC, 1 East, Room 1-3140, 10 Center Drive, MSC 1109, Bethesda, Maryland 20892-1109. E-mail: NiemanL{at}nih.gov.

Context: Inferior petrosal sinus sampling (IPSS) best discriminates between the two causes of ACTH-dependent Cushing’s syndrome, Cushing’s disease (CD) and ectopic ACTH secretion (EAS). However, when sampling is not available, adjunctive diagnostic tests might be helpful. Neuroendocrine tumors may secrete chromogranin A (CgA), calcitonin (CT), procalcitonin (ProCT), a fragment of the amino terminus of procalcitonin (NProCT), and/or ACTH.

Objective: The aim of the study was to evaluate the ability of serum CgA, CT, ProCT, or NProCT values to distinguish CD from EAS.

Design and Setting: We conducted a prospective pilot study at a clinical research center.

Subjects and Methods: Serum ProCT, NProCT, and CgA were measured in six patients with occult EAS diagnosed by IPSS, 25 CD patients, and 11 patients with histologically proven EAS.

Results: Nine EAS patients (53%) had at least one value above the reference range, including CgA alone (n = 4), ProCT alone (n = 3), CgA and ProCT (n = 1), and NProCT and ProCT (n = 1). Of nine (36%) CD patients with one or two abnormal values, seven had increased ProCT only, one had increased NProCT only, and one had increased CgA and ProCT. CgA had a positive predictive value of 83% and a negative predictive value of 70% for the diagnosis of EAS; other markers showed less discrimination. On pituitary magnetic resonance imaging, no EAS patient had an abnormality, whereas 21 of 25 patients with CD had a mass.

Conclusion: These preliminary results suggest that an abnormal CgA and normal pituitary magnetic resonance imaging favor the diagnosis of EAS, but normal tumor markers do not exclude the diagnosis.