In a patient with a 2.5 cm pituitary macroadenoma, lack of cortisol suppression after dexamethasone suppression test, modestly elevated 24‑hour urinary free cortisol, normal‑range ACTH, and class III obesity, what is the diagnosis and recommended management?

Diagnosis: ACTH-Dependent Cushing's Disease (Pituitary Macroadenoma)

This patient has Cushing's disease caused by an ACTH-secreting pituitary macroadenoma, confirmed by the combination of a 2.5 cm pituitary adenoma, detectable ACTH (15 pg/mL), lack of cortisol suppression after dexamethasone, and elevated 24-hour urinary free cortisol. 1, 2

Diagnostic Reasoning

Confirming ACTH-Dependent Cushing's Syndrome

• Any ACTH level >5 pg/mL indicates ACTH-dependent Cushing's syndrome with high certainty, ruling out adrenal causes where ACTH would be suppressed (<5 pg/mL) 1, 2
• The ACTH of 15 pg/mL definitively establishes this as ACTH-dependent disease 1
• The 24-hour urinary free cortisol of 70 μg/day (modestly elevated above normal upper limit of ~50 μg/day) confirms hypercortisolism 3
• Post-dexamethasone cortisol of 5.3 μg/dL (failure to suppress below 1.8 μg/dL) confirms autonomous cortisol production 3, 4

Localizing to Pituitary Source

• A pituitary adenoma ≥10 mm (this patient has 25 mm) with confirmed ACTH-dependent hypercortisolism strongly indicates Cushing's disease and does not require bilateral inferior petrosal sinus sampling (BIPSS) before proceeding to surgery 1, 2
• Pituitary macroadenomas account for only 2% of Cushing's disease cases but are definitively diagnosed when imaging shows a large adenoma with biochemical confirmation 5, 6

Understanding the Atypical Biochemical Pattern

• ACTH-secreting macroadenomas characteristically show less robust biochemical features than microadenomas, with mean ACTH levels around 135 ng/L in macroadenomas versus 45 ng/L in microadenomas 6
• This patient's relatively modest ACTH (15 pg/mL) and UFC (70 μg/day) are consistent with macroadenomas, which paradoxically often present with milder hypercortisolism despite larger tumor size 3, 6
• The lack of dexamethasone suppression is expected, as macroadenomas show significantly less suppression (57.6%) compared to microadenomas (74.4%) 6

Management Approach

Primary Treatment: Transsphenoidal Surgery

Transsphenoidal adenomectomy is the first-line treatment for Cushing's disease, though cure rates are significantly lower for macroadenomas (30-44%) compared to microadenomas (70-90%). 3, 5, 7

Pre-operative Considerations

• Medical therapy to normalize cortisol before surgery is increasingly used to reduce perioperative complications, particularly in patients with severe hypercortisolism 3, 7
• For this patient with class III obesity and relatively mild hypercortisolism, consider pre-operative medical therapy with:
  • Osilodrostat or metyrapone (adrenal steroidogenesis inhibitors) for rapid cortisol normalization within hours to days 3
  • Ketoconazole as an alternative, with response typically within days 3
  • Cabergoline is less appropriate here given slower onset and lower efficacy 3

Surgical Prognosis Factors

• Unfavorable prognostic factors in this patient include:
  • Large tumor size (2.5 cm) - significantly reduces cure rates 5, 6
  • Relatively high baseline ACTH (though modest, any elevation predicts worse outcomes) 5
  • Assess for cavernous sinus invasion on MRI, which dramatically worsens surgical outcomes 5

Post-Operative Management

If Surgery Achieves Remission

• Monitor for hypoadrenalism requiring glucocorticoid replacement (dexamethasone or hydrocortisone) 3
• Lifelong surveillance is mandatory as recurrence occurs in 10-20% of initially cured patients 7
• Serial measurements of 24-hour UFC and late-night salivary cortisol every 3-6 months initially, then annually 3

If Surgery Fails to Achieve Remission (High Likelihood)

Given the low cure rate for macroadenomas, prepare for adjuvant therapy:

1. Second-line medical therapy 3:

   • Osilodrostat or metyrapone (first choice for reliable cortisol control)
   • Pasireotide (consider if residual tumor present for potential tumor shrinkage, but high risk of hyperglycemia - critical concern given obesity) 3
   • Cabergoline (if mild residual disease and tumor shrinkage desired) 3
   • Mifepristone (for severe metabolic complications, but requires clinical monitoring as cortisol levels remain elevated) 3

2. Repeat surgery if residual tumor is clearly identified and accessible 5

3. Pituitary radiotherapy (conventional or stereotactic):

   • Effective in 50-60% of patients over 2-5 years 3
   • Consider early if surgery unsuccessful, particularly given macroadenoma size 5

4. Bilateral adrenalectomy as definitive treatment if medical therapy fails and radiotherapy is ineffective or contraindicated 3, 7

Critical Monitoring Parameters

Metabolic Complications

• Class III obesity significantly increases perioperative risk and complicates cortisol assessment 3
• Screen for and aggressively manage:
  • Type 2 diabetes or impaired glucose tolerance 3
  • Hypertension 3
  • Hypokalemia (particularly if using mifepristone) 3
  • Venous thromboembolism risk 7

Tumor Surveillance

• Serial pituitary MRI every 6-12 months to monitor for tumor regrowth, particularly if not cured surgically 3, 7
• If using mifepristone, monitor for tumor progression as ACTH levels will rise (seen in 3 patients with macroadenomas up to 25 months) 3

Important Caveats

• Do not perform BIPSS in this patient - the macroadenoma ≥10 mm with confirmed ACTH-dependent hypercortisolism is sufficient for diagnosis 1, 2
• Measure dexamethasone levels if repeating suppression testing to exclude false positives from malabsorption, particularly relevant given obesity 3, 1
• Thyroid function requires close monitoring if medical therapy is initiated, with adjustment of thyroid hormone replacement as needed 3
• All concomitant medications must be reviewed for drug-drug interactions, particularly with ketoconazole or mifepristone 3