Secretion of ectopic ACTH by nonpituitary tumors accounts for about 10% of cases of Cushing syndrome. In many instances the responsible tumor is a small-cell carcinoma of the lung, although other neoplasms, including carcinoids, medullary carcinomas of the thyroid, and PanNETs, have been associated with the syndrome. In addition to tumors that elaborate ectopic ACTH, occasional neuroendocrine neoplasms produce ectopic CRH, which, in turn, causes ACTH secretion and hypercortisolism. As in the pituitary variant, the adrenal glands undergo bilateral cortical hyperplasia secondary to elevated ACTH, but the rapid downhill course of patients with these cancers often cuts short the adrenal enlargement.
Primary adrenal neoplasms, such as adrenal adenoma and carcinoma, and rarely, primary cortical hyperplasia, are responsible for about 15% to 20% of cases of endogenous Cushing syndrome, also designated ACTH-independent Cushing syndrome, because the adrenals function autonomously. The biochemical hallmark of adrenal Cushing syndrome is elevated levels of cortisol and low serum levels of ACTH. In most cases, adrenal Cushing syndrome is caused by a unilateral adrenocortical neoplasm, which may be benign (adenoma) or malignant (carcinoma). Primary cortical hyperplasia of the adrenal cortices is a rare cause of Cushing syndrome. There are two variants of this entity; the first presents as macronodules of varying sizes (typically less than 3 cm in diameter) and the second as micronodules (1–3 mm).
MORPHOLOGYThemainlesionsofCushingsyndromearefoundinthepituitaryandadrenalglands.ThepituitaryinCushingsyndromeshowschangesthatvarywithdifferentcauses.Themostcommonalteration,resultingfromhighlevelsofendogenousorexogenousglucocorticoids,istermedCrookehyalinechange.Inthiscondition,thenormalgranular,basophiliccytoplasmoftheACTH-producingcellsintheanteriorpituitaryisreplacedbyhomogeneous,lightlybasophilicmaterial.Thisalterationistheresultoftheaccumulationofintermediatekeratinfilamentsinthecytoplasm.InpituitaryCushingsyndrome,thereisanadenoma(describedunderdiseasesofthepituitary).
Fig.20.35Diffusehyperplasiaoftheadrenalgland(bottom) contrastedwithanormaladrenalgland(top). Inacross-section,theadrenalcortexisyellowandthickened,andasubtlenodularityisevident.TheabnormalglandwasfromapatientwithACTH-dependentCushingsyndrome,inwhombothadrenalglandswerediffuselyhyperplastic.ACTH, Adrenocorticotropichormone.
Morphologicchangesintheadrenalglandsalsodependonthecauseofthehypercortisolismandinclude:(1)corticalatrophy, (2)diffusehyperplasia,(3)macronodularormicronodularhyperplasia,or(4)anadenomaorcarcinoma.
Inpatientsinwhomthesyndromeresultsfromexogenousglucocorticoids,suppressionofendogenousACTHresultsinbilateralcorticalatrophy,duetoalackofstimulationofthezonafasciculataandzonareticularisbyACTH.Thezonaglomerulosaisofnormalthicknessinsuchcases,becausethisportionofthecortexfunctionsindependentlyofACTH.Incasesofendogenoushypercortisolism,bycontrast,theadrenalseitherarehyperplasticorcontainacorticalneoplasm.