Surgical Versus Conservative Management for Subclinical Cushing Syndrome in Adrenal Incidentalomas: A Prospective Randomized Study

Antonio Toniato, MD; Isabella Merante-Boschin, MD; Giuseppe Opocher, MD; Maria R. Pelizzo, MD; Francesca Schiavi, MD; Enzo Ballotta, MD


Annals of Surgery. 2009;249(3):388-391. 

In This Article

Abstract and Introduction


Objective: To compare the clinical outcome of patients with subclinical Cushing syndrome (SCS) due to an adrenal incidentaloma (the autonomous hypersecretion of a small amount of cortisol, which is not enough to cause clinically-evident disease) who underwent surgery or were managed conservatively.
Summary Background Data: The most appropriate management of SCS patients is controversial, either adrenalectomy or close follow-up being recommended for their treatment.
Methods: Over a 15-year period, 45 SCS patients were randomly selected to undergo surgery (n = 23) or conservative management (n = 22). All surgical procedures were laparoscopic adrenalectomies performed by the same surgeon. All patients were followed up (mean, 7.7 years; range, 2-17 years) clinically by 2 experienced endocrinologists 6 and 12 months after surgery and then yearly, or yearly after joining the trial, particularly monitoring diabetes mellitus (DM), arterial hypertension, hyperlipidemia, obesity, and osteoporosis. The study end point was the clinical outcome of SCS patients who underwent adrenalectomy versus those managed conservatively.
Results: All 23 patients in the surgical arm had elective surgery. Another 3 patients randomly assigned to conservative management crossed over to the surgical group due to an increasing adrenal mass > 3.5 cm. In the surgical group, DM normalized or improved in 62.5% of patients (5 of 8), hypertension in 67% (12 of 18), hyperlipidemia in 37.5% (3 of 8), and obesity in 50% (3 of 6). No changes in bone parameters were seen after surgery in SCS patients with osteoporosis. On the other hand, some worsening of DM, hypertension, and hyperlipidemia was noted in conservatively-managed patients.
Conclusions: Based on the results of this study, laparoscopic adrenalectomy performed by skilled surgeons appears more beneficial than conservative management for SCS patients complying with our selection criteria. This trial is registered with Australian Clinical Trials Registry number, ANZCTR12608000567325.


In the last 20 years, the widespread use of diagnostic tools such as ultrasound, computed tomography (CT) and, more recently, magnetic resonance imaging has increased the rate of detection of adrenal neoplasms during the diagnosis or treatment of unrelated conditions.[1,2,3] Managing these accidentally-detected adrenal masses, called incidentalomas, will be a growing clinical challenge in our aging society because of its higher prevalence in the elderly.[4] The natural history of incidentalomas suggests that up to 25% will increase in size by at least 1 cm and up to 20% will develop hormone overproduction.[5] Whereas most of incidentalomas are clinically silent and nonfunctioning, 5-20% of them, accounting for a mean rate of 7.8%, may autonomously produce adrenocortical hormone (cortisol) in mild entity, not enough to cause clinically-evident disease.[5] Although the diagnostic criteria adopted vary slightly in different study protocols, refined laboratory tests enables subclinical hypercortisolism to be disclosed remarkably often, detectable biochemically as hypothalamic-pituitary-adrenal (HPA) axis functional derangements.[3,6,7,8,9] This condition has been defined as subclinical Cushing syndrome (SCS), in which diabetes mellitus (DM),[10,11] hypertension,[6,11,12] hyperlipidemia (all cardiovascular risk factors), and osteoporosis[9] are often present, though their evolution towards a clinically overt syndrome is rare.[3,6,7,8,9,10,11,12,13]

Given the variety of diagnostic and treatment methods currently adopted, the most appropriate management of SCS patients remains controversial, with either adrenalectomy or close follow-up being recommended.[3,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22] Although SCS patients may be at greater risk of metabolic disorders and cardiovascular disease, no large studies have demonstrated that these patients benefit from surgery. We undertook a prospective randomized clinical study to compare the benefits of surgery or conservative management for SCS patients.


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