Spontaneous remission is rare in
ectopic ACTH syndrome (EAS). We describe four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a
tumor. Patients were treated with
ketoconazole alone or with
mitotane and/or
metyrapone to control hypercortisolemia.
Dexamethasone was added when a block and replace strategy was used. Treatment with steroidogenesis inhibitors for 3-10 years in these patients was followed by a prolonged period of remission (15-60 months). During remission, the first patient had an elevated
ACTH, low
cortisol and 24-h urinary free
cortisol (UFC), and adrenal
atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low
ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic
tumor. They did not have a history of cyclicity and case 3 has been in remission for ~5 years, making cyclic
Cushing's syndrome less likely. Case 4, with a history of cyclic
hypercortisolism, had normal to slightly elevated
ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of
ACTH by the ectopic
tumor. Spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors; a drug holiday may be warranted during chronic
therapy to evaluate this. The pathophysiology remains unclear but may involve several different mechanisms.