Diagnosis and Management of Cushing's Syndrome: Results of an Italian Multicentre Study

Abstract

The past 45 yr' experience with Cushing's syndrome (CS) has led to the awareness of its complex nature and, by the same token, brought about an increase in the diagnostic and therapeutic dilemmas. We carried out a retrospective multicentre study on the diagnostic work-up and treatment in 426 patients with CS, subdivided as follows: 288 with Cushing'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 recorded in about 10% of patients with CS. In 28% of patients with ACTH-independent CS, basal ACTH concentrations were within the normal range but did not respond to CRH stimulation. Measurement of ACTH levels by immunoradiometric assay, rather than by RIA, offered a greater chance of recognizing patients 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 CS. An 80% decrease in cortisol levels after 8 mg dexamethasone overnight, or in UFC values after the classical 2-day administration, excluded an ectopic secretion but carried a low negative predictive value given the high number of nonsuppressors among patients with CD. Pituitary imaging identified an adenoma in 61% of patients with CD. At inferior petrosal sinus sampling, an ACTH centre: periphery gradient after CRH less than 3, correctly classified all patients with ectopic secretion but misdiagnosed 15% of 76 patients with CD. Transsphenoidal pituitary surgery, the standard therapy for CD, resulted in complete remission (appearance of clinical signs of adrenal insufficiency associated with low/normal UFC excretion and, when available, low/normal morning plasma ACTH and cortisol levels) in 69% of patients. The overall relapse rate after pituitary surgery was 17%. The probability of relapse-free survival, 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 postoperative baseline plasma ACTH and cortisol peak after CRH. No relapses were observed among patients who did not respond to CRH. Other therapeutic approaches for CD, such as pituitary irradiation and medical therapy, resulted in normalization of cortisol secretion in about half of treated cases. In summary, an accurate selection of the available diagnostic tools leads to the correct diagnosis in the majority of patients with CS. The therapeutic 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.

THERAPY OF ENDOCRINE DISEASE: Outcomes in patients with Cushing's disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence

“…With regard to the outcomes analyzed by surgical experience, the highest recurrence rate (13.6%) was seen when ten or fewer patients were operated per year of study duration (in 18 studies), while the lowest rate (6.7%) was seen when 31-40 patients were operated per year of study duration (rZK0.3; PZNS; albeit these data are from only two studies (29,48)). In contrast to remission, a trend toward an increase in recurrence rate could be noted over time, with the upper limit of recurrence rate ranges increasing steadily by decade of study publication, suggesting poorer outcomes or better reporting of recurrence rates (rZ0.8; PZNS; Table 1).…”

“…A variety of definitions of remission of Cushing's disease after initial microscopic TSS is used in the literature: symptoms of hypercortisolism remitted (25), a continuous need for corticosteroid replacement for O6 months after TSS (26), no need for additional treatment because of clinical remission of the disease (27), resolution of symptoms and signs of hypercortisolism (28) or of clinical features (16,19), clinical evidence of eucortisolemia (23), appearance of clinical signs of adrenal insufficiency (29), regression of the clinical signs (30), presence of clinical and laboratory signs of adrenal insufficiency (17,22), and reversal of the clinical stigmata (31). Clinical parameters were never used alone to define remission; clinical evaluation was always combined with serum cortisol, UFC, and/or LDDST biochemical tests ( Table 1).…”

Dosagem de cortisol e cortisona livres urinários empregando cromatografia líquida associada a espectrometria de massa em tandem (LC-MS/MS)

“…A disseminação da metodologia deverá reposicionar a dosagem de cortisol livre dentre as téc-nicas utilizadas para o screening de hipercortisolismo endógeno (síndrome de Cushing). Isto por que a alta especificidade analítica permite um diagnóstico mais preciso do que aquele obtido com os imunoensaios mais comuns, tornando a dosagem, já aceita como uma das mais úteis, ao lado de cortisol pós-depressão com dexametasona e cortisol salivar à meia-noite (38)(39)(40)(41)(42), ainda mais atrativa. O método aqui descrito apresenta a vantagem adicional de permitir a dosagem concomitante da cortisona livre, e conseqüentemente o estudo da atividade da enzima 11β-HSD2.…”

Cushing's syndrome associated with a nested stromal epithelial tumor of the liver: hormonal, immunohistochemical, and molecular studies

“…Ectopic ACTH syndrome (EAS) represents 9-18% of all causes of Cushing's syndrome (1)(2)(3). EAS is mainly associated with either highly malignant tumors such as small cell lung carcinoma or less aggressive tumors such as pulmonary or mediastinal carcinoids, but also pancreatic and thymic carcinoids, gastrinoma, pheochromocytoma, and medullary thyroid cancer.…”