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Cyclical Cushing’s Syndrome in a Patient with a Bronchial Neuroendocrine Tumor (Typical Carcinoid) Expressing Ghrelin and Growth Hormone Secretagogue Receptors

Division of Endocrinology (G.Ar., T.M., B.K., G.Ap., S.F., C.C., A.M., M.B.), Department of Internal Medicine, University of Ancona, 60100 Ancona, Italy; Department of Pathology (I.B.), University of Ancona, 60100 Ancona, Italy; and Division of Endocrinology (F.M.), Department Internal Medicine, University of Padua, 35128 Padua, Italy

Address all correspondence and requests for reprints to: Dr. Giorgio Arnaldi, Clinica di Endocrinologia, Azienda Ospedaliera Umberto I, Sede Torrette, 60100 Ancona, Italia. E-mail: (office) g.arnaldi{at}ao-umbertoprimo.marche.it, (home) arnaldi.giorgio{at}libero.it.

A 56-yr-old woman was referred with a diagnosis of Cushing’s disease. Hypertension and severe hypokalemia were present and high urinary free cortisol/cortisone ratio was detected, raising a suspicion of an ectopic ACTH syndrome. Inferior petrosal sinus sampling, thoracic computed tomography, and octreotide scans were negative. Remission and relapse periods lasting 3–4 months were observed during the 3.5 yr of follow-up. Finally a thoracic computed tomography scan showed a basal paracardic nodule in the left lung. After surgery, a well-differentiated neuroendocrine tumor (typical bronchial carcinoid) was diagnosed, staining positively for ACTH. RT-PCR revealed expression of proopiomelanocortin, CRH receptor, and V3 vasopressin receptor. Somatostatin receptor type 1, 2, 3, and 5 mRNA was detected only in tumoral tissue. Interestingly, we observed the simultaneous presence of ghrelin and both GH secretagogue (GHS) receptors (1a and 1b) mRNA in tumoral tissue but not in the normal lung. This finding correlates with the in vivo ACTH hyperresponsiveness to hexarelin (a GHS).

This is the first report of a cyclical ectopic ACTH-secreting tumor with an in vivo ACTH response to hexarelin coupled with the tumoral expression of ghrelin and GHS receptors. This finding might imply an autocrine/paracrine modulatory effect of ghrelin in bronchial ACTH-secreting tumors.

Abbreviations: CS, Cushing’s syndrome; CT, computed tomography; CV, coefficient of variation; DDAVP, 1-disamino-ß-D-arginine vasopressin; F, cortisol; GHS, GH secretagogue; hCRH, human CRH; 11HSD2, 11 hydroxysteroid dehydrogenase type 2; HSSTR, human somatostatin receptor; MRI, magnetic resonance imaging; NSE, neuron-specific enolase; POMC, proopiomelanocortin; UFE, urinary free cortisone; UFF, urinary free cortisol.

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