This protocol applies to patients with ACTH-dependent Cushing's syndrome caused by an ectopic ACTH-secreting tumor in whom initial surgical treatment did not achieve adequate cortisol control — or whose disease is occult or metastatic at presentation.
Cushing's syndrome has multiple causes; in this setting, hypercortisolism is driven by ectopic ACTH secretion from a non-pituitary tumor. The common causes of Cushing's syndrome include intrinsic adrenal gland abnormalities and ACTH secretion from a corticotrope tumor or from an ectopic tumor (EAS). Here, the ectopic source is the identified driver.
The preceding step — localization and surgical resection of the ectopic ACTH-secreting tumor with node dissection as appropriate — did not achieve remission. Remission is defined as morning serum cortisol < 5 µg/dL (< 138 nmol/L) or urine free cortisol < 10–20 µg/d within 7 days of tumor resection.
This protocol describes the structured management pathway taken after that failure. It also covers occult or metastatic ectopic ACTH-secreting disease where upfront surgical cure is not achievable.
When surgical remission has not been achieved — or the tumor is occult or metastatic — the protocol outlines medical, surgical, and targeted options directed at cortisol control. A central pharmacological approach involves agents that inhibit adrenal steroidogenesis. Additional procedural and targeted options exist depending on the disease presentation. The complete selection criteria, sequencing, and full regimen are available in the full protocol.
Control of hypercortisolism with normalization of cortisol levels off medication.
The common causes of CS include intrinsic adrenal gland abnormalities and ACTH secretion from a corticotrope tumor (CD) or from an ectopic tumor (EAS).
We recommend localizing and resecting ectopic ACTH-secreting tumors with node dissection as appropriate.
We recommend steroidogenesis inhibitors under the following conditions: as second-line treatment after TSS in patients with CD, either with or without RT/radiosurgery; as primary treatment of EAS in patients with occult or metastatic EAS; and as adjunctive treatment to reduce cortisol levels in adrenocortical carcinoma (ACC).
We suggest bilateral adrenalectomy for occult or metastatic ectopic ACTH secretion (EAS) or as a life-preserving emergency treatment in patients with very severe ACTH-dependent disease who cannot be promptly controlled by medical therapy.
We suggest targeted therapies to treat ectopic ACTH syndrome.
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