What is the most likely cause of Cushingoid features with hypercortisolism and elevated Adrenocorticotropic hormone (ACTH) levels?

Most Likely Cause: Pituitary Adenoma (Cushing's Disease)

The combination of Cushingoid features with elevated cortisol AND elevated ACTH indicates ACTH-dependent Cushing's syndrome, and a pituitary adenoma (Cushing's disease) is by far the most likely cause, accounting for 75-80% of cases in children and 49-71% in adults. 1

Understanding the Laboratory Pattern

The key to this diagnosis lies in the ACTH level:

• Elevated ACTH with hypercortisolism definitively indicates ACTH-dependent Cushing's syndrome - meaning the excess cortisol is being driven by ACTH from either a pituitary source or an ectopic tumor 2
• Any ACTH level >5 ng/L is detectable and confirms ACTH-dependency with high certainty 2
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing's disease specifically 2

Why Each Answer is Right or Wrong

A) Pituitary Adenoma (CORRECT)

• This is the correct answer - pituitary adenomas cause 75-80% of ACTH-dependent Cushing's syndrome cases 1
• Most are microadenomas (98% of cases), frequently ≤2 mm in diameter 1
• The elevated ACTH directly points to a pituitary or ectopic source, and pituitary is statistically dominant 1, 2

B) Adrenal Adenoma (INCORRECT)

• Adrenal adenomas cause ACTH-independent Cushing's syndrome 2
• In adrenal adenoma, ACTH would be low or undetectable, not elevated 2
• The autonomous cortisol production from the adrenal tumor suppresses pituitary ACTH secretion 2

C) Iatrogenic (INCORRECT)

• Iatrogenic Cushing's results from exogenous glucocorticoid administration 3
• Exogenous steroids would suppress both ACTH and endogenous cortisol production 2
• This patient has elevated endogenous cortisol WITH elevated ACTH, ruling out iatrogenic causes

D) Carcinoid Syndrome (INCORRECT - but requires nuance)

• While carcinoid tumors (particularly thymic neuroendocrine tumors) CAN produce ectopic ACTH and cause elevated ACTH with hypercortisolism 4, they are rare
• Ectopic ACTH syndrome accounts for only ~2% of Cushing's syndrome cases 4
• Carcinoid syndrome itself (flushing, diarrhea) is distinct from ectopic ACTH production and only occurs in ~2% of thymic carcinoids 4
• Given the statistical probability, pituitary adenoma is far more likely than ectopic ACTH

Diagnostic Next Steps

After establishing ACTH-dependent Cushing's syndrome:

• Pituitary MRI with thin slices (3T preferred) should be performed to identify the adenoma 2
• If adenoma ≥10 mm is found, this strongly confirms Cushing's disease 2
• If MRI is negative or shows lesion <6 mm, bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard to differentiate pituitary from ectopic ACTH sources 1, 2
• BIPSS diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation 2

Critical Pitfall to Avoid

Do not assume ectopic ACTH syndrome without proper workup - while ectopic sources exist (lung, thymus, pancreas, bowel) 4, the overwhelming statistical likelihood with elevated ACTH is pituitary adenoma 1. Only pursue ectopic workup if BIPSS indicates a non-pituitary source or if clinical features suggest it (very high cortisol, profound hypokalemia) 2.