In a female patient with rapid (3‑4 month) onset of severe Cushingoid features, marked hypercortisolism and elevated ACTH, how can we differentiate a pituitary ACTH‑secreting adenoma (Cushing disease) from an ectopic ACTH‑producing tumor?

Distinguishing Pituitary Adenoma from Ectopic ACTH-Secreting Tumors

In a patient with rapid-onset severe Cushingoid features and elevated ACTH, bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard test to definitively distinguish Cushing disease from ectopic ACTH syndrome, achieving 96-100% sensitivity and near-100% specificity when performed correctly. 1, 2

Clinical Context and Initial Assessment

The clinical presentation provides important clues before proceeding to definitive testing:

• Rapid onset (3-4 months) with severe hypercortisolism strongly suggests ectopic ACTH syndrome rather than pituitary disease, as ectopic sources typically cause more aggressive disease progression 3, 4
• Profound hypokalemia, very high urinary free cortisol levels, and male gender are additional clinical features favoring an ectopic source 5
• However, pituitary adenomas account for 75-80% of all ACTH-dependent Cushing syndrome, making this statistically more likely despite the rapid presentation 2, 3

Diagnostic Algorithm

Step 1: Pituitary MRI (3T preferred)

• Obtain high-resolution 3T pituitary MRI with thin slices and gadolinium contrast as the initial imaging study 1
• If adenoma ≥10 mm is detected, proceed directly to transsphenoidal surgery without further testing 1, 2
• If adenoma 6-9 mm is found, perform CRH or desmopressin stimulation testing for additional confirmation 1, 2
• Approximately one-third of pituitary MRIs remain negative in confirmed Cushing disease, as microadenomas are frequently ≤2 mm in diameter 1, 2

Step 2: Dynamic Biochemical Testing

When MRI shows no lesion or a lesion <6 mm, dynamic testing can provide supportive evidence:

• CRH stimulation test: Increased plasma ACTH and cortisol following CRH administration usually indicates Cushing disease, though well-differentiated neuroendocrine tumors may also respond 1
• Desmopressin stimulation test: Increased ACTH and cortisol suggests pituitary source, as V1b receptors are overexpressed in corticotroph adenomas but typically absent in ectopic tumors 1
• Using more than one dynamic test improves diagnostic accuracy 1
• Important caveat: None of these tests reach 100% specificity, and results may be discordant in up to one-third of patients 1, 5

Step 3: Bilateral Inferior Petrosal Sinus Sampling (BIPSS) - The Gold Standard

BIPSS is mandatory when pituitary MRI shows no adenoma, a lesion <6 mm, or when dynamic testing results are discordant: 1, 2, 5

Diagnostic Criteria:

• Central-to-peripheral ACTH ratio ≥2:1 at baseline OR ≥3:1 after CRH/desmopressin stimulation confirms pituitary source 1, 2, 5
• Ratio <2:1 baseline or <3:1 after stimulation suggests ectopic tumor 1, 5
• Simultaneous prolactin measurement from petrosal sinuses confirms adequate catheter placement and improves diagnostic accuracy 1, 2
• Inter-petrosal ACTH gradient ≥1.4 after stimulation may suggest tumor lateralization, though concordance with surgical findings ranges only 58-87.5% 2

Critical Prerequisites:

• Active hypercortisolism must be confirmed on the morning of BIPSS to avoid false negatives in patients with cyclic disease 2
• All steroidogenesis-inhibiting medications must be discontinued prior to BIPSS, with appropriate wash-out periods 2
• BIPSS should only be performed in specialized centers by experienced interventional radiologists due to operator-dependent accuracy and potential complications 1, 2

Step 4: Localization of Ectopic Source (if BIPSS indicates peripheral source)

If BIPSS confirms an ectopic source:

• Obtain neck-to-pelvis thin-slice CT scan to identify the tumor 1, 5
• 68Ga-DOTATATE PET/CT has 65% detection rate for localizing ectopic ACTH-secreting neuroendocrine tumors not visible on conventional imaging 5, 6
• The most common ectopic sources are bronchial carcinoids (up to 40% of cases), small-cell lung carcinoma, pancreatic neuroendocrine tumors, thymic carcinoids, medullary thyroid carcinoma, and pheochromocytomas 2, 3
• Occult tumors occur in 12-38% of ectopic ACTH syndrome cases, requiring long-term follow-up 3

Non-Invasive Alternative Approach

A combination strategy may be considered when BIPSS is unavailable or contraindicated:

• Combine CRH stimulation, desmopressin stimulation, and pituitary MRI findings 1
• If diagnosis remains equivocal, proceed to whole-body CT imaging 1
• This approach has reasonable accuracy but is less definitive than BIPSS 1

Common Pitfalls to Avoid

• Do not rely on high-dose dexamethasone suppression test alone, as it has low overall accuracy despite historical use 1
• Tumor size does not correlate with hypercortisolism severity in Cushing disease—patients with larger adenomas frequently present with milder hypercortisolism 1
• Well-differentiated neuroendocrine tumors may express CRH and V1b receptors, potentially causing false-positive dynamic test results that mimic pituitary disease 1
• Never perform BIPSS without confirming active hypercortisolism on the same day, as cyclic disease can produce false-negative results 2
• Differences in tumor type, patient age, sex, and severity of hypercortisolism can all influence test outcomes 1

Management During Diagnostic Work-Up

Given the severe presentation described:

• Initiate steroidogenesis inhibitors (ketoconazole, metyrapone) promptly to control severe hypercortisolism and prevent complications 2
• Monitor blood pressure, glucose, and electrolytes closely 2
• Screen for and treat Cushing-related complications including hypertension, diabetes, infections, and osteoporosis 2
• Delayed diagnosis increases morbidity and mortality from cardiovascular disease, infections, and metabolic complications, so pursue the diagnostic work-up expeditiously 2