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Dopamine Receptor Expression and Function in Corticotroph Ectopic Tumors

Departments of Internal Medicine (R.P., D.F., W.W.d.H., S.W.J.L., L.J.H.) and Pathology (R.R.d.K.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Departments of Molecular and Clinical Endocrinology and Oncology (R.P., A.F., G.L., A.C.), "Federico II" University of Naples, 80131 Naples, Italy; Department of Nuclear Medicine, European Institute of Oncology (L.B.), 20141 Milan, Italy; and Department of Endocrinological and Metabolic Sciences and Center of Excellence for Biomedical Research (D.F.), University of Genoa, 16132 Genoa, Italy

Address all correspondence and requests for reprints to: Rosario Pivonello, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University, Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail: rpivone{at}tin.it.

Background: Dopamine receptor (DR) expression and dopamine agonist (DA) effectiveness have never been demonstrated in neuroendocrine tumors associated with ectopic ACTH syndrome (EAS).

Aim: The aim of the current study was to evaluate DR and particularly D₂ subtype expression in neuroendocrine tumors associated with EAS and to evaluate the in vivo effectiveness of the DA cabergoline in the treatment of EAS.

Patients and Methods: Six ACTH-secreting neuroendocrine tumors, including four lung, one pancreatic, and one thymic carcinoid, were used for the evaluation of D₂ expression by immunohistochemistry. DR subtypes and D₂ isoforms and number were evaluated by RT-PCR in three cases of persistent EAS after surgery. These patients were treated with cabergoline at the dose of 3.5 mg/wk for 6 months. Clinical parameters, hormonal levels, and tumor size were monitored during the treatment period.

Results: At immunohistochemistry, D₂ was expressed in five (83.3%) tumors. At RT-PCR, D₂ was confirmed in all three cases but at variable numbers, whereas D₄ was expressed in two cases. D_2long was expressed in all three cases, together with D_2short in one case. A normalization of urinary cortisol levels was found in two patients (66.7%) after 3 months of treatment. However, treatment escape was demonstrated in one of these patients afterward.

Conclusion: The results of this study demonstrated that DR are expressed in neuroendocrine tumors associated with EAS and that cabergoline treatment could be effective in controlling cortisol excess in a subgroup of patients with EAS. Further studies on a larger number of patients are mandatory to confirm the usefulness of DA in EAS.

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