Background: Cushing syndrome (CS) represents a challenging disease. The major difficulty is to distinguish between the two main etiologies of ACTH-dependent hypercortisolism. However, in rare cases, the concomitant presence of both an ACTH-dependent and a primary adrenal disease should be considered.
Case report: We evaluated a 67-year-old woman for a severe ACTH-dependent CS (midnight serum cortisol 332 ng/ml; urinary free cortisol [UFC] 3000 mcg/day; cortisol after low-dose dexamethasone suppression test: 387 ng/ml, ACTH between 32 and 51 pg/ml), with metabolic syndrome and hypokalemia. Her past medical history was remarkable for right nephrectomy for renal clear cell carcinoma. During the oncological follow-up, a 45 mm mediastinic mass, suggestive for thymoma, and bilateral adrenal masses (right 40 mm; left 15 mm) were detected. Laboratory tests showed lack of cortisol response to high-dose dexamethasone suppression test (179 ng/ml) and lack of cortisol and ACTH response to CRH stimulation. Even if dynamic tests and clinical features were suggestive for an ectopic ACTH secretion, ACTH levels were detectable, but not as high as expected for an ectopic disease. Therefore, we considered mandatory to exclude a pituitary etiology of hypercortisolism: MRI showed a small lesion suggestive for pituitary microadenoma, but inferior petrosal sinus sampling ruled out an ACTH gradient between petrosal sinus and peripheral vein, suggesting an ectopic ACTH secretion. The patient underwent a 68Ga-PET-CT, which showed an increased uptake corresponding to the known thymoma. To justify the detectable, but not high ACTH levels, we hypothesized the coexistence of an ectopic ACTH secretion (thymoma) and an autonomous hyperfunctioning bilateral adrenal hyperplasia, which could cause a partial inhibition of ACTH secretion. The patient underwent thymectomy. Histology showed a neuroendocrine tumor, with foci of atypical carcinoid, and focal reactivity for ACTH at immuno-histochemistry. In support to our hypothesis of a double etiology of CS, the degree of hypercortisolism considerably improved and the patient did not experience hypocortisolism, as expected after successful surgery for ACTH-secreting tumor. In fact, in this case, the partial autonomous adrenal activity (subclinical CS) probably compensated the expected hypocortisolism related to the fall of ACTH levels. Three months after surgery, the patient stopped anti-diabetic and anti-hypertensive therapy, while laboratory evaluation showed a normalization of UFC.
Conclusion: This case shows how the challenging diagnostic work-up of CS can be complicated further by the coexistence of more than one etiology and highlights the importance of applying a stepwise and methodical approach to its diagnosis.
18 - 21 May 2019
European Society of Endocrinology