Introduction: Cushings syndrome (CS) is a medical condition resulting from a chronic excessive exposure to glucocorticoids. ACTH-dependent CS are mostly caused by pituitary adenoma (about 80-85% of the cases) and, in a lower proportion, by ectopic ACTH secretion (about 10-15% of the cases). The exact origin of an ectopic secretion of ACTH is not always easy to identify. The most common locations are bronchus, lung and pancreas but it can also be located in thymus, thyroid and within a pheochromocytoma (1,2). We describe here the case of an ACTH-dependent hypercorticism due to astill unidentified tumor.
Background: A Cushings syndrome was diagnosed in a 57-year-old man with obesity, melanoderma, uncontrolled diabetes and amyotrophy. He had a medical history of metabolic syndrome with high blood pressure controlled with triple-combination anti-hypertensive drugs and type 2 diabetes treated with Metformin and Semaglutide. Despite the treatment with Semaglutide, he gained 10 kg during the last 5 months. Urinary free cortisol measurements were highly increased (6xULN). The overnight dexamethasone suppression test confirmed CS, plasma level of ACTH was in favor of ACTH- dependent CS and pituitary MRI showed a micronodule of 4mm. CRH and Desmopressine tests were both in favor of ACTH-dependent CS of ectopic origin. The 68Ga-DOTATATE PET/CT showed 2 lesions overexpressing somatostatin subtype 2 receptor (SSTR2): one in the pancreatic tail and one, with a lesser intensity, within a right pulmonary nodule. Our hypothesis was an ectopic ACTH secretion caused by this pancreatic tumor. Biopsy of the lesion demonstrated grade 2 neuroendocrine tumor. ACTH immunostaining was negative. As the general condition of the patient did not allow surgery, a radiofrequency ablation of the lesion was scheduled after a treatment with Etomidate to allow a rapid return to eucorticism. Post-procedure, ACTH and Cortisol didnt decrease as expected and a treatment with Ketoconazole was started. Given these results, a Petrosal sinus sampling was performed and was in favor of an ectopic secretion of ACTH. We therefore suspected that either the treatment had not been sufficiently effective or that there was another source of ectopic ACTH. The pulmonary nodule biopsy demonstrated aspecific inflammatory tissues.
Discussion: Ectopic ACTH secretion is a rare cause of CS (1). When the dynamic tests are in favor of an ectopic secretion, start a complex work to identify the source of the secretion. Medical imagings do not always reveal the origin of the ectopic secretion. Through our clinical case, we would like to discuss the difficulty of the clinical diagnosis, the exams needed and the risk of incidentaloma which can make the discovery of the origin of the secretion even more complex. According to the literature, 16% of the ectopic ACTH secretion remains unidentified. If the disease is located, surgery is the treatment of choice. Medical treatment should be reserved for cases where surgery cannot be offered. In some cases when hypercorticism is still uncontrolled with medication or surgery, the bilateral adrenalectomy is an option but implies a lifetime hormonal substitution (3). Even when surgery is not possible, the prognosis of paraneoplasic secretion of unidentified tumor remains good (1,4).
References: 1. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushings syndrome due to ectopic corticotropin secretion: twenty years experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005 Aug;90(8):4955-62. 2. Doi M, Sugiyama T, Izumiyama H, Yoshimoto T, Hirata Y. Clinical features and management of ectopic ACTH syndrome at a single institute in Japan. Endocr J. 2010;57(12):1061-9. 3. Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Holland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M. Treatment of adrenocorticotropin-dependent Cushings syndrome: a consensus statement. J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62. 4. Howlett TA, Drury PL, Perry L, Doniach I, Rees LH, Besser GM. Diagnosis and management of ACTH-dependent Cushings syndrome: comparison of the features in ectopic and pituitary ACTH production. Clin Endocrinol (Oxf). 1986 Jun;24(6):699-713.