How to differentiate between pituitary, adrenal, and ectopic hypercortisolism, or Cushing's disease and Cushing syndrome?

Differentiating Pituitary, Adrenal, and Ectopic Hypercortisolism

The differentiation between pituitary Cushing's disease, adrenal Cushing's syndrome, and ectopic ACTH syndrome relies on a sequential diagnostic algorithm: first confirm hypercortisolism, then measure ACTH to determine ACTH-dependent versus ACTH-independent disease, followed by imaging and bilateral inferior petrosal sinus sampling (BIPSS) when needed to localize the source. 1, 2

Step 1: Confirm Hypercortisolism

Before attempting to differentiate the source, hypercortisolism must be confirmed using one of these first-line tests 1, 2:

• 24-hour urinary free cortisol (more than one measurement) 1
• Late-night salivary cortisol (more than one measurement) 1, 3
• 1 mg overnight dexamethasone suppression test (normal suppression is cortisol <1.8 μg/dL) 1, 2

Critical pitfall: Always exclude iatrogenic Cushing's syndrome from exogenous glucocorticoid use before any biochemical testing, as failure to do so leads to unnecessary testing without benefit 1

Step 2: Measure ACTH to Determine Dependency

Morning (08:00-09:00h) plasma ACTH measurement is the definitive test to distinguish ACTH-dependent from ACTH-independent disease 2:

ACTH-Dependent Cushing's Syndrome (Pituitary or Ectopic Source)

• ACTH >5 ng/L indicates ACTH-dependent disease with high certainty 2
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing's disease specifically 2
• This includes both pituitary adenomas (Cushing's disease, 70% of cases) and ectopic ACTH-secreting tumors (15% of cases) 4

ACTH-Independent Cushing's Syndrome (Adrenal Source)

• ACTH low or undetectable (<5 ng/L) indicates primary adrenal disease 2, 3
• Proceed directly to adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 2
• This accounts for approximately 15% of Cushing's syndrome cases 4

Step 3: Differentiate Pituitary from Ectopic ACTH (for ACTH-Dependent Cases)

Initial Imaging

Perform high-quality pituitary MRI (3T preferred over 1.5T) with thin slices to detect pituitary adenomas 2:

• If pituitary adenoma ≥10 mm is detected and dynamic testing is consistent with Cushing's disease, BIPSS is not necessary for diagnosis 1
• If adenoma 6-9 mm, consider CRH stimulation testing 2
• If no adenoma or lesion <6 mm, proceed to BIPSS 1, 2

Clinical Clues Suggesting Ectopic ACTH Syndrome

Look for these features that favor ectopic over pituitary sources 1, 5:

• Profound hypokalemia (present in all ectopic cases but only 10% of Cushing's disease) 5
• Very high urinary free cortisol levels 1
• Metabolic alkalosis with hypokalemia 1
• Rapid onset of symptoms 1
• Weight loss (occurs in ~10% of ectopic ACTH cases, unusual in pituitary disease) 1
• Male sex (ectopic ACTH more common in males) 1
• Skin hyperpigmentation (more prominent with ectopic ACTH) 1

If high suspicion for ectopic ACTH syndrome exists, perform neck-to-pelvis thin-slice CT scan to search for bronchial carcinoid or small cell lung cancer 1

Dynamic Testing to Distinguish Pituitary from Ectopic Sources

CRH and desmopressin stimulation tests can help differentiate 1:

• Increased plasma ACTH and cortisol following CRH or desmopressin administration usually indicates Cushing's disease (pituitary source) 1
• Blunted or absent response suggests ectopic ACTH syndrome 1
• Most pituitary corticotroph adenomas express CRH, V2/V3 vasopressin, and V1b receptors, while most ectopic ACTH-secreting tumors do not 1

Important caveat: Well-differentiated neuroendocrine tumors may also express these receptors, potentially causing false-positive results 1

High-dose dexamethasone suppression test (>50% cortisol suppression suggests pituitary source) has low overall accuracy and is less reliable 1

Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard test to definitively distinguish pituitary from ectopic ACTH-secreting tumors and should be performed in almost all ACTH-dependent cases except those with pituitary macroadenomas 1, 6:

Diagnostic criteria 1, 2:

• Central-to-peripheral ACTH ratio ≥2:1 before stimulation suggests pituitary source
• Central-to-peripheral ACTH ratio ≥3:1 after CRH or desmopressin stimulation confirms pituitary source
• Ratio <2 before or <3 after stimulation suggests ectopic tumor

Critical requirements for BIPSS 1, 2:

• Must be performed in a specialized center by an experienced interventional radiologist due to potential patient risk 1
• Patient must be hypercortisolemic at the time of IPSS 1
• Medical therapy with steroidogenesis inhibitors must be stopped before BIPSS 2
• Prolactin measurement during BIPSS can improve diagnostic accuracy 1
• Inter-petrosal sinus ACTH gradient ≥1.4 after stimulation may provide tumor lateralization information 2

Advanced Imaging for Ectopic ACTH Syndrome

68Ga-DOTATATE PET imaging is useful for localizing ectopic ACTH-secreting neuroendocrine tumors 1:

• Localizes approximately 65% of ectopic ACTH-secreting tumors 1
• Particularly helpful for tumors not seen on conventional CT imaging 1
• Greater sensitivity for small tumors compared to older imaging modalities 1
• Caveat: False positives can occur due to chronic inflammation, and a positive scan does not definitively prove the tumor is the ACTH source 1

Non-Invasive Diagnostic Approach

A combination of CRH and desmopressin stimulation testing plus MRI, followed by whole-body CT if equivocal, correctly diagnosed Cushing's disease in approximately half of patients in specialized centers, potentially eliminating the need for BIPSS 1. However, this approach is currently limited to specialized centers and should not replace BIPSS when diagnosis remains uncertain 1.

Key Diagnostic Pitfalls

• No single test reaches 100% specificity, and results may be discordant in up to one-third of patients 1
• Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 2
• Pseudo-Cushing's states (severe obesity, alcoholism, depression) can cause false-positive screening results 2
• Incidental pituitary lesions occur in up to 10% of the general population; a visible pituitary lesion does not automatically confirm Cushing's disease in the setting of ectopic ACTH syndrome 1
• Occult ectopic ACTH secretion may be impossible to distinguish from pituitary Cushing's disease without BIPSS 5