Diagnosis and management of Cushing's syndrome: Results of an Italian multicentre study

The past 45 yr' experience with Gushing's syndrome (GS) has led to the awar eness of its complex nature and, by the same token, brought about an increa se in the diagnostic and therapeutic dilemmas. We carried out a retrospecti ve multicentre study on the diagnostic work-up and treatment in 426 patient s with CS, subdivided as follows: 288 with Gushing's disease (CD), 80 with an adrenal adenoma, 24 with an adrenal carcinoma, 25 with ectopic ACTH and/ or CRH secretion, and 9 with ACTH-independent nodular adrenal hyperplasia. Normal urinary free cortisol (UFC) values among multiple collections were r ecorded in about 10% of patients with GS. In 28% of patients with ACTH-inde pendent CS, basal ACTH concentrations were within the normal range but did not respond to CRH stimulation. Measurement of ACTH levels by immunoradiome tric assay, rather than by RLA, offered a greater chance of recognizing pat ients with ACTH-independent CS or ectopic secretion. A 50% increase in ACTH or cortisol levels after CRH yielded a diagnostic accuracy of 86% and 61%, respectively, in the differential diagnosis of ACTH-dependent GS. An 80% d ecrease in cortisol levels after 8 mg dexamethasone overnight, or in UFC va lues after the classical 2-day administration, excluded an ectopic secretio n but carried a low negative predictive value given the high number of nons uppressors among patients with GD. Pituitary imaging identified an adenoma in 61% of patients with GD. At inferior petrosal sinus sampling, an ACTH ce ntre: periphery gradient after CRH less than 3, correctly classified all pa tients with ectopic secretion but misdiagnosed 15% of 76 patients with CD. Transsphenoidal pituitary surgery, the standard therapy for GD, resulted in complete remission (appearance of clinical signs of adrenal insufficiency associated with low/normal UFC excretion and, when available, low/normal mo rning plasma ACTH and cortisol levels) in 69% of patients. The overall rela pse rate after pituitary surgery was 17%. The probability of relapse-free s urvival, as assessed by Kaplan-Meier analysis, was 95% at 12 months, 84% at 2 yr, and 80% at 3 yr. Risk of relapse was significantly correlated with p ostoperative baseline plasma ACTH and cortisol peak after CRH. No relapses were observed among patients who did not respond to CRH. Other therapeutic approaches for GD, such as pituitary irradiation and medical therapy, resul ted in normalization of cortisol secretion in about half of treated cases. In summary, an accurate selection of the available diagnostic tools leads t o the correct diagnosis in the majority of patients with GS. The therapeuti c options for CD, adrenal carcinoma, and ectopic secretion are, as yet, not fully satisfactory. The high incidence of relapse after pituitary surgery calls for a prolonged follow-up.