Recognition and Management of Ectopic ACTH Secreting Tumors

Abstract

Ectopic ACTH syndrome (EAS), in which Cushing syndrome is caused by excessive ACTH secretion from a tumor located outside of the pituitary, is associated with an impaired quality of life and an increased mortality rate. Outcomes can be improved with successful tumor localization and resection, which often proves difficult. In order to distinguish EAS from Cushing disease, a significantly more common condition where excessive ACTH is secreted from a pituitary tumor, bilateral inferior petrosal sinus sampling (IPSS) is often necessary. Correct performance and interpretation of IPSS hence becomes crucial to avoid inappropriate future interventions, including surgical procedures. Once an ectopic source of ACTH is confirmed biochemically, identifying the causative tumor is often challenging since they can be located in unexpected areas and potentially be very small. Additionally, EAS carries a risk of severe hypercortisolism, which sometimes needs urgent treatment to avoid disastrous outcomes. The cases here illustrate pitfalls in diagnostic biochemical testing, describe helpful imaging strategies to improve the chances of tumor detection, and review available options to rapidly normalize severe hypercortisolism in critical situations.

Keywords: Cushing; Cushing disease; DOTATATE; IPSS; ectopic ACTH syndrome.

Figure 1.

Tests to determine the source of excessive ACTH-secretion require corticotrope suppression. In normal physiology (left), hypothalamic CRH induces ACTH secretion from pituitary corticotropes. In Cushing disease (center) and ectopic ACTH syndrome (right), tumoral sources of ACTH induce excessive adrenal cortisol production, which inhibits healthy CRH- and ACTH-secreting neurons in the hypothalamus and pituitary, respectively. The width of the arrows and font sizes indicate the greater amount of hormone secretion, adrenal stimulation (by ACTH), and negative feedback to the hypothalamus and pituitary (by cortisol) in patients with Cushing syndrome.

Figure 2.

Use of gated cardiac and functional imaging to detect ectopic sources of ACTH. The right-sided pericardiac culprit lesion (arrows) was missed on chest computed tomography (A) but detected on later gated cardiac magnetic resonance imaging (B), with avidity being confirmed on a ⁶⁸Ga-DOTATATE positron emission tomography scan (C).

Figure 3.

Functional imaging is critical to detect ectopic sources of ACTH. The culprit lesion (arrows) was not identified on computed tomography (A) until the images were carefully rereviewed after a focus of tracer avidity was noted on ⁶⁸Ga-DOTATATE (B) and ¹⁸F-DOPA (C) positron emission tomography scans.