Diagnostic and Treatment Approach for Cushing's Syndrome with Detectable ACTH and Partially Empty Sella
For a patient with Cushing's syndrome, detectable ACTH levels, and a partially empty sella, bilateral inferior petrosal sinus sampling (BSIPSS) is strongly recommended to confirm a pituitary source of ACTH excess, especially when MRI findings are equivocal due to the empty sella. 1
Diagnostic Algorithm
Step 1: Confirm Hypercortisolism (Cushing's Syndrome)
- Perform at least two of the following tests to confirm hypercortisolism 1:
- 24-hour urinary free cortisol (UFC) collection for 3 days (>193 nmol/24h)
- Serum cortisol circadian rhythm study (midnight cortisol ≥50 nmol/l)
- Late-night salivary cortisol (based on local assay cut-off)
- Low-dose dexamethasone suppression test (LDDST) (cortisol ≥50 nmol/l)
Step 2: Determine ACTH Dependency
- Measure morning (08:00-09:00h) plasma ACTH levels 1:
- Detectable ACTH (>5 ng/l or >1.1 pmol/l) indicates ACTH-dependent Cushing's syndrome
- A cut-off value of 29 ng/l (6.4 pmol/l) has 70% sensitivity and 100% specificity for diagnosing Cushing's disease 1
Step 3: Localize the Source of ACTH Excess
- Perform high-resolution pituitary MRI with and without contrast 1:
- Note that partially empty sella may complicate interpretation
- Pituitary MRI has 63% sensitivity and 92% specificity for adenoma detection 1
- Perform CRH stimulation test (1.0 μg/kg IV) 1:
- ≥20% increase in cortisol from baseline supports pituitary origin
- Sensitivity 74-100%
Step 4: Confirm Pituitary Source with BSIPSS
- BSIPSS is essential when 1:
- No adenoma is identified on MRI (common with partially empty sella)
- To distinguish between Cushing's disease and ectopic ACTH syndrome
- BSIPSS criteria for confirming pituitary source 1:
- Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin
- Central-to-peripheral ACTH ratio ≥3:1 after CRH/desmopressin
- BSIPSS should only be performed at specialized centers by experienced interventional radiologists 1
- Confirm hypercortisolemia immediately before BSIPSS to ensure active disease phase 1
Treatment Algorithm
First-Line Treatment: Surgery
- Transsphenoidal surgery (TSS) is first-line treatment for Cushing's disease 1, 2
- Special considerations with empty sella 3:
- Higher risk of CSF leakage and other complications
- Remission can still be achieved in most cases (5 of 6 patients in one study)
Second-Line Options (if surgery fails or is contraindicated)
Medical Therapy
- Steroidogenesis inhibitors 1, 4:
- Ketoconazole (400-1200 mg/day) - most commonly used due to availability and tolerability
- Mitotane for more severe cases
- Pituitary-directed therapy 4, 5:
- Pasireotide (0.6-0.9 mg SC twice daily) - FDA-approved for Cushing's disease
- Monitor for hyperglycemia, QT prolongation, and hypocortisolism
Radiation Therapy
- Consider for persistent hypercortisolism after incomplete tumor resection 1
- Stereotactic radiosurgery (SRS) preferred over conventional radiotherapy 1
- Monitor for hypopituitarism, which occurs in 25-50% of patients 1
Bilateral Adrenalectomy
- Consider when other treatments have failed 1
- Provides immediate control of cortisol excess 1
- Requires lifelong glucocorticoid and mineralocorticoid replacement 1
- Risk of corticotroph tumor progression (25-40% after 5-10 years) requires long-term monitoring 1
Special Considerations for Partially Empty Sella
- Partially empty sella is found in approximately 22% of Cushing's disease patients 6
- The association between empty sella and Cushing's disease may be coincidental 3
- Surgical complications may be higher in patients with empty sella 3:
- CSF leakage
- Diabetes insipidus
- Hypopituitarism
- Medical therapy with ketoconazole may be considered as first-line treatment when 3:
- No adenoma is visible on MRI
- Patient has contraindications for surgery
- The empty sella increases surgical risk