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INTRODUCTION

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Cushing’s syndrome is a symptomatic manifestation of a wide variety of disease processes culminating in hypercortisolism, only a few of which, including ectopic ACTH syndrome (EAS), necessitate the attention of a surgical oncologist.1 In the classical setting of EAS, the diagnosis begins under the supervision of an endocrinologist, and the careful application of a diagnostic algorithm of laboratory testing, imaging, and/or interventional procedures often helps identify a source.2 However, EAS can also present in a paraneoplastic fashion in a patient with a known malignancy, and surgical oncologists may be called upon to identify a potential source. This chapter will briefly review the physiology of the hypothalamic-pituitary-adrenal (HPA) axis and Cushing’s syndrome, discuss the diagnosis of EAS and its descriptive classifiers, and outline management strategies for the care of patients with EAS.

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BACKGROUND

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The HPA axis is complex feedback regulatory mechanism by which the body maintains cortisol homeostasis and responds to episodes of stress. Neuroendocrine cells within the paraventricular nucleus of the hypothalamus secrete corticotropin-releasing hormone (CRH) and vasopressin. These peptides stimulate the anterior lobe of the pituitary gland to release adrenocorticotropic hormone, which in turn, stimulates the adrenal cortex to produce glucocorticoid hormones, including cortisol. The presence of cortisol downregulates production of CRH and ACTH in the hypothalamus and pituitary gland, respectively, completing a negative feedback loop with a somewhat predictable circadian rhythm of circulating serum cortisol in the absence of dysregulation of the HPA axis (Fig. 51-1).3

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FIGURE 51-1

The hypothalamic-pituitary-adrenal axis. A. In a physiologic state, release of cortisol from the adrenal cortex provides negative feedback to the hypothalamus and pituitary (green arrows), to decrease the release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), respectively. B. In EAS, cortisol feedback inhibits release of CRH and pituitary ACTH, but the ectopic source of ACTH is unaffected, resulting in adrenal hyperplasia and large excess circulating cortisol. Ectopic source depicted by red mass and superphysiologic amounts are depicted by the red arrows.

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Dysregulation can occur as a normal physiologic response to stress, as a result of exogenous administration of glucocorticoids, or by overproduction of CRH or ACTH by tumors. When sustained dysregulation leads to hypercortisolism, specific metabolic effects can be seen, identified as Cushing’s syndrome. The most common cause is exogenous glucocorticoid usage exceeding physiologic requirements and can often be ascertained by obtaining a careful medication history. Endogenous forms of the syndrome are divided into ACTH-dependent and ACTH-independent causes. Overall, ACTH-dependent cases account for 80% to 85% of endogenous causes, the majority of which are Cushing’s disease; ectopic ACTH production is responsible for about 20% of ACTH-dependent Cushing’s syndrome.1

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The first case of EAS was described in 1928, though it was initially noted as an association of two independent conditions.4 As more cases appeared in the literature, ...

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