Most Likely Diagnosis: Pituitary Adenoma (Cushing's Disease)
When both ACTH and cortisol are elevated, the most likely diagnosis is a pituitary adenoma causing Cushing's disease, which accounts for 75-80% of ACTH-dependent Cushing's syndrome cases in children/adolescents and 49-71% in adults. 1, 2
Diagnostic Algorithm for Elevated ACTH and Cortisol
Step 1: Determine ACTH Dependency
- Elevated or normal ACTH levels (>1.1 pmol/L or >5 ng/L) confirm ACTH-dependent Cushing's syndrome, immediately excluding adrenal adenoma (Answer B) and exogenous steroid use (Answer C), both of which suppress ACTH to undetectable levels 3, 1, 4
- This finding indicates the excessive cortisol originates from either pituitary or ectopic ACTH secretion 1, 5
Step 2: Differentiate Pituitary vs. Ectopic Sources
Pituitary adenoma (Cushing's disease) is statistically dominant:
- Represents the overwhelming majority of ACTH-dependent cases (75-80% in pediatric populations, 49-71% in adults) 1, 2
- Microadenomas ≤2 mm account for 98% of cases, with macroadenomas being rare (2-5% in children, 10% in adults) 3, 2
Ectopic ACTH secretion (Answer D) is much less common:
- Accounts for a small minority of ACTH-dependent cases 4, 6
- Thymic sources represent only up to 2% of all Cushing's syndrome cases 1, 5
- Other ectopic sources include lung, thyroid, pancreas, and bowel tumors 5
Step 3: Clinical Context Favoring Pituitary Disease
Key distinguishing features that support pituitary adenoma:
- Response to high-dose dexamethasone suppression (cortisol suppression >50%) suggests pituitary source 4, 6
- Positive CRH stimulation test (cortisol increase ≥20%) has 74-100% sensitivity for pituitary disease 3
- Discrete pituitary lesion on MRI (detected in approximately 63-70% of cases) 3, 4
Features suggesting ectopic ACTH:
- Autonomous ACTH secretion with lack of response to high-dose dexamethasone 7
- Absence of pituitary lesion on MRI with positive imaging for extrapituitary tumor 5
- Extremely rapid onset of severe hypercortisolism with hypokalemia 4
Step 4: Confirmatory Testing When Needed
Bilateral inferior petrosal sinus sampling (IPSS) with CRH stimulation is definitive:
- Central-to-peripheral ACTH ratio ≥3 after CRH confirms pituitary source with 100% sensitivity 3, 5
- This test is reserved for cases where imaging is non-contributive or dynamics are equivocal 4, 6
Common Pitfalls to Avoid
- Do not assume ectopic ACTH based solely on elevated ACTH levels - the statistical probability strongly favors pituitary adenoma as the first consideration 1, 2
- Do not be misled by negative pituitary MRI - microadenomas are frequently too small to visualize (≤2 mm), yet still represent the most common cause 3, 2
- Do not confuse autonomous ACTH secretion with ectopic source - rare ectopic pituitary adenomas in the sphenoid sinus can mimic ectopic ACTH syndrome 7
Answer Selection
A. Pituitary adenoma is the correct answer - it represents the most common cause of ACTH-dependent Cushing's syndrome by a substantial margin, making it the most likely diagnosis when both ACTH and cortisol are elevated 1, 2, 4