1839 1840 1841 ## Adrenocorticotropic Hormone-Dependent Cushing Syndrome 1842 1843 Overview. ACTH-dependent hypercortisolism accounts for 80% to 85% of endogenous Cushing syndrome. Approximately 80% of ACTH-dependent disease results from primary pituitary pathology and is known as Cushing disease. Ectopic ACTH production is the other main cause of ACTH-dependent hypercortisolism (Newell-Price et al., 2006). Ectopic CRH syndrome is a third cause of ACTH-dependent Cushing syndrome and is extremely uncommon (see Fig. 106.6) (Orth, 1995). 1844 1845 Cushing Disease. Described by the neurosurgical pioneer Harvey Cushing in 1932, Cushing disease causes hypercortisolism through excessive secretion of ACTH by the pituitary gland (Cushing, 1932). The condition accounts for nearly 70% of endogenous Cushing syndrome. The most common culprit is a corticotropin-producing microadenoma. Large macroadenomas 1 cm or greater are found in only about 5% of cases (Newell-Price et al., 2006). Fifteen percent of functional pituitary adenomas exhibit the ability to secrete ACTH (Shimon and Melmed, 1998). Hyperplasia of ACTH-producing cells and pituitary carcinoma can also oversecrete ACTH but are extremely rare (Orth, 1995). Up to two-thirds of individuals with Cushing disease are female (Scott and Orth, 1990). 1846 1847 Ectopic Adrenocorticotropic Hormone Syndrome. Production of ACTH by nonpituitary tumors can also result in hypercortisolism. These corticotropin-producing tissues are nearly always malignant and account for approximately 10% of Cushing syndrome (Porterfield et al., 2008). Liddle et al. first described the phenomenon in the early 1960s and termed it ectopic ACTH syndrome (Meador et al., 1962; Scott and Orth, 1990). The timing and onset of hypercortisolism varies and can precede the diagnosis of an extra-adrenal malignancy by many years, resulting in diagnostic difficulties and the clinical conundrum wherein a subclinical pituitary adenoma is suspected but not radiographically identified (Aniszewski et al., 2001). Moreover, hypercortisolism in end-stage debilitated cancer patients is almost certainly undiagnosed (Orth, 1995). As a result of higher ACTH levels, the adrenal glands of patients with ectopic ACTH syndrome are usually more markedly hyperplastic and thereby larger than those of patients with Cushing disease (Fig. 106.7) (Jenkins et al., 1999). Table 106.4 summarizes primary malignancies implicated in ectopic ACTH production, which notably includes pheochromocytoma. 1848 1849 Ectopic Corticotropin-Releasing Hormone. Production of CRH by malignancies is extremely rare and is responsible for less than 1% 1850 1851 1852 1853 *TABLE 106.4 Sources of Ectopic Adrenocorticotropic Hormone* 1854 1855 1856 < [... Output truncated due to length. 5102 tokens/18893 characters removed ...]

PARAMETER	CURRENT STUDY	FINDLING AND TYRRELL, 1986^a	IMURA ET AL., 1975	DOPPMAN ET AL., 1989	HOWLETT ET AL., 1986
Number of patients	106	49	30	28	16
No tumor found (%)	16	12		32
Islet cell tumor (%)	16	4	7	11	13
Bronchial carcinoid tumor (%)	25	49	7	46