Abstract
We describe a patient with Cushing’s syndrome and metastatic small cell lung cancer. The plasma ACTH concentrations were markedly elevated (91.6 pmol/L), and the AM Cortisol did not suppress by >50% overnight after administration of 8 mg dexamethasone, both consistent with the ectopic ACTH syndrome. Immunohistochemical studies of a single metastatic tumor specimen, however, demonstrated an absence of ACTH and yet an abundance of corticotropin-releasing hormone (CRH). In addition, radioimmunoassay of the patient’s plasma demonstrated persistently elevated CRH concentrations. The majority of the plasma CRH immunoreactivity exhibited the same chromatographic mobility as synthetic r/h CRH (1–41) on HPLC. Failure to evaluate the tumor tissue for the presence of ACTH and/or CRH would have led to the erroneous conclusion that this patient’s Cushing’s syndrome resulted from paraneoplastic ACTH production. We conclude that immunoassay of plasma for both ACTH and CRH and, perhaps, immunostaining of tumor samples are required to distinguish between the ectopic ACTH and CRH syndromes.
Similar content being viewed by others
References
Carpenter P.C. Diagnostic evaluation of Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 17: 445, 1988.
Carey R.M., Varma S.K., Drake C.R., Thorner M.O., Kovacs K., Rivier J., Vale W. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing’s syndrome. N. Engl. J. Med. 311: 13, 1984.
Belsky J.L., Cuello B., Swanson L.W., Simmons D.M., Jarrett R.M., Braza F. Cushing’s syndrome due to ectopic production of corticotropin-releasing factor. J. Clin. Endocrinol. Metab. 60: 496, 1985.
Schteingart D.E., Lloyd R.V., Akil H., Chandler W.F., Ibarra-Perez G., Rosen S.G., Ogletree R. Cushing’s syndrome secondary to ectopic corticotropin-releasing hormone-adrenocorticotropin secretion. J. Clin. Endocrinol. Metab. 63: 770, 1986.
Asa S.L., Kovacs K., Tindall G.T., Barrow D.L., Horvath E., Vecsei P. Cushing’s disease associated with an intrasellar gangliocytoma producing corticotrophin-releasing factor. Ann. Intern. Med. 101: 789, 1984.
Fjellestad-Paulsen A., Abrahamsson P.A., Bjartell A., Grino M., Grimelius L. Hedeland H., Falkmer S. Carcinoma of the prostate with Cushing’s syndrome Acta Endocrinol. (Copenh.) 119: 506, 1988.
Gerl H., Knappe G., Rohde W., Stahl F., Wolff H., Martin H. Cushing’s syndrome in CRF-producing mediastinal carcinoid. Dtsch. Med. Wockenschr. 115: 332, 1990.
Dluhy R.G. Case records of the Massachusetts General Hospital. Case 52–1987. N. Engl. J. Med. 317: 1648, 1987.
Tourniaire J., Rebattu B., Conte-Devolx B., Trouillas J., Grino M., Berger-Dutrieux N., Peix J.L., Pugeat M. Cushing’s syndrome caused by ectopic production of CRF by a medullary carcinoma of the thyroid body. Ann. Endocrinol. 49: 61, 1988.
Upton G.V., Amatruda T.T. Evidence for the presence of tumor peptides with corticotropin-releasing-factor-like activity in the ectopic ACTH syndrome. N. Engl. J. Med. 285: 419, 1971.
Suda T., Demura H., Demura R., Wakabayash I., Nomura K., Odagiri E., Shizume K. Corticotropin-releasing factor-like activity in ACTH producing tumors. J. Clin. Endocrinol. Metab. 44: 440, 1977.
Hashimoto K., Takahara J., Ogawa N., Yunoki S., Ofuji T., Arata A., Kanda S., Terada K. Adrenocorticotropin, ß-lipotrophin, ß-endorphin, and corticotropin-releasing factor-like activity in an adrenocorticotropin-producing nephroblastoma. J. Clin. Endocrinol. Metab. 50: 461, 1980.
Zarate A., Kovacs K., Flores M., Moran C., Felix I. ACTH and CRF-producing bronchial carcinoid associated with Cushing’s syndrome. Clin. Endocrinol. (Oxf.) 24: 523, 1986.
Suda T., Kondo M., Totani R., Hashimoto N., Suzuki M., Imaki T., Oba Y., Tomqri N., Yajima F., Sumitomo T., Nakagami Y., Ushiyama T., Demura H., Shizume K., Upton G.V. Ectopic adrenocorticotropin syndrome caused by lung cancer that responded to corticotropin-releasing hormone. J. Clin. Endocrinol. Metab. 63: 1047, 1986.
Hashimoto K., Suemaru S., Hattori T., Sugawara M., Ota Z., Takata S., Hamaya K., Doi K., Chretien M. Multiple endocrine neoplasia with Cushing’s syndrome due to paraganglioma producing corticotropin-releasing factor and adrenocorticotropic Acta Endocrinol. (Copenh.) 113: 189, 1986.
Raux Demay M.C., Proeschel M.F., de Keyzer Y., Bertagna X., Luton J.P., Girard F. Characterization of human corticotrophin-releasing hormone and pro-opiomelanocortin-related peptides in a thymic carcinoid tumour responsible for Cushing’s syndrome. Clin. Endocrinol. (Oxf.) 29: 649, 1988.
Nawata H., Higuchui K., Ikuyama S., Kato K-I., Ibayashi H., Mimura K., Sueishi K, Zingami H., Imura H. Corticotropin-releasing hormone and adrenocorticotropin-producing pituitary carcinoma with metastases to the liver and lung in a patient with Cushing’s disease. J. Clin. Endocrinol. Metab. 71: 1068, 1990.
Biemond P., de Jong F.H., Lamberts S.W.J. Continuous dexamethasone infusion for seven hours in patients with the Cushing syndrome. Ann. Intern. Med. 112: 738, 1990.
Calogero A.E., Bernardini R., Margioris A.N., Bagdy G., Gallucci W.T., Munson P.J., Tamarkin L., Tomai T.P., Brady L., Gold P.W., Chrousos G.P. Effects of serotonergic agonists and antagonists on corticotropin-releasing hormone secretion by explanted rat hypothalami. Peptides 10: 189, 1989.
Schurmeyer T.H., Avgerinos P.C., Gold P.W., Gallucci W.T., Tomai T.P., Cutler Jr. G.B., Loriaux D.L., Chrousos G.P. Human corticotropin-releasing factor in man: pharmacokinetic properties and dose-response of plasma adrenocorticotropin and Cortisol secretion. J. Clin. Endocrinol. Metab. 59: 1103, 1984.
Hsu S.M., Raine L., Fanger H. A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies. Am. J. Clin. Pathol. 75: 734, 1981.
Hsu S.M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J. Histochem. Cytochem. 29: 577, 1981.
Oldfield E.H., Doppman J.L., Nieman L.K., Chrousos G.P., Miller D.L., Katz D.A., Cutler G.B., Loriaux D.L Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N. Engl. J. Med. 325: 897, 1991.
Liddle G.W. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 20: 1539, 1960.
Flack M.R., Oldfield E.H., Cutler G.B., Zweig M.H., Malley J.D., Chrousos G.P., Loriaux D.L., Nieman L.K. Urine free Cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome. Ann. Intern. Med. 116: 211, 1992.
Bruno O.D., Rossi M.A., Contreras L.N., Gomez R.M., Galparsoro G., Cazado E., Kral M., Leber B., Arias D. Nocturnal high-dose dexamethasone suppression test in the aetiological diagnosis of Cushing’s syndrome. Acta Endocrinol. (Copenh.) 109: 158, 1985.
Tyrrell J.B., Findling J.W., Aron D.C., Fitzgerald P.A., Forsham P.H. An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing’s syndrome. Ann. Intern. Med. 104: 180, 1986.
Ashcraft M.W., VanHerle A.J., Vener S.L., Geffner D.L. Serum Cortisol levels in Cushing’s syndrome after low- and high-dose dexamethasone suppression. Ann. Intern. Med. 97: 21, 1982.
Author information
Authors and Affiliations
Additional information
The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Defense or other Departments of the US Government.
Rights and permissions
About this article
Cite this article
Auchus, R.J., Mastorakos, G., Friedman, T.C. et al. Corticotropin-releasing hormone production by a small cell carcinoma in a patient with ACTH-dependent Cushing’s syndrome. J Endocrinol Invest 17, 447–452 (1994). https://doi.org/10.1007/BF03347737
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03347737