What is the recommended evaluation and treatment approach for a patient suspected of having Cushing's syndrome?

Evaluation and Treatment Approach for Cushing's Syndrome

The recommended evaluation for suspected Cushing's syndrome begins with screening tests including overnight 1-mg dexamethasone suppression test (DST), late-night salivary cortisol (LNSC), and 24-hour urinary free cortisol (UFC), followed by plasma ACTH measurement to differentiate ACTH-dependent from ACTH-independent causes, with treatment tailored to the specific etiology. 1

Diagnostic Approach

Initial Screening Tests

• First-line screening tests (at least one should be performed):
  • Overnight 1-mg dexamethasone suppression test (DST)
  • Late-night salivary cortisol (LNSC) - sensitivity >90%, specificity 100%
  • 24-hour urinary free cortisol (UFC) - reflects overall cortisol production 1

Determining the Cause

1. Measure plasma ACTH levels to differentiate:

   • ACTH-dependent causes (normal to elevated ACTH):
     • Pituitary adenoma (Cushing's disease) - accounts for 60-70% of cases 2
     • Ectopic ACTH-secreting tumors (lung, thyroid, pancreas, bowel)
   • ACTH-independent causes (suppressed ACTH):
     • Adrenal adenoma
     • Adrenal carcinoma
     • Bilateral adrenal hyperplasia 3, 1

2. For ACTH-dependent cases, perform:

   • Dynamic tests to differentiate pituitary from ectopic sources:
     • High-dose dexamethasone suppression test (>50% cortisol suppression suggests pituitary origin)
     • CRH stimulation test (>50% increase in ACTH/cortisol suggests pituitary origin)
     • Desmopressin test (ACTH increase suggests pituitary origin) 1
   • Imaging:
     • MRI of pituitary
     • CT of chest, abdomen, and pelvis if ectopic source suspected 3, 1
   • Bilateral inferior petrosal sinus sampling (IPSS) when results are equivocal:
     • Central-to-peripheral gradient ≥2 basal or ≥3 post-stimulation confirms pituitary origin
     • Absence of gradient suggests ectopic source 1

3. For ACTH-independent cases, perform:

   • Adrenal imaging (CT or MRI)
   • Assess for malignancy if tumor >5 cm, inhomogeneous with irregular margins 3

Treatment Approach

1. Surgical Management (First-Line)

• For Cushing's disease (pituitary origin):
  • Transsphenoidal surgery 1
• For adrenal adenoma/carcinoma:
  • Laparoscopic adrenalectomy for benign tumors when feasible
  • Open adrenalectomy for suspected malignancy 3, 1
• For ectopic ACTH-secreting tumors:
  • Surgical resection of the tumor when possible 3

2. Medical Management (Second-Line or Adjunctive)

• Adrenostatic agents:
  • Ketoconazole (400-1200 mg/day) - most commonly used due to availability and tolerability 3, 1
  • Mitotane - particularly for adrenal carcinoma 3
  • Osilodrostat - FDA-approved for adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative 4
• Pituitary-directed therapy:
  • Pasireotide - for patients with persistent or recurrent Cushing's disease 5
• For ectopic ACTH syndrome:
  • Octreotide may be considered if the tumor is Octreoscan-positive 3

3. Other Treatment Options

• Radiation therapy:
  • For pituitary tumors when surgery is unsuccessful 6
  • Consider adjuvant radiation for adrenal carcinoma, particularly with tumor spillage or close margins 3
• Bilateral adrenalectomy:
  • For refractory ACTH-dependent Cushing's syndrome
  • For patients with bilateral adrenal hyperplasia 3, 1

Post-Treatment Management

• Glucocorticoid replacement:
  • Required after successful surgery until HPA axis recovery
  • Hydrocortisone (15-25 mg daily in divided doses) 1
• Monitoring:
  • Follow-up imaging and biomarkers every 3-6 months for functioning tumors 3
  • Annual clinical screening for patients not managed surgically 1

Special Considerations

• Cyclic Cushing's syndrome: Perform testing during active hypercortisolism phase 1
• Women on estrogen-containing contraceptives: May have false positive DST results 1
• Pediatric patients: Cushing's disease accounts for 75-80% of cases in children over age 6, while adrenal causes are more common in younger children 1

Comorbidity Management

• Type 2 diabetes (present in up to 30% of patients)
• Hypertension, osteoporosis, dyslipidemia, and proximal myopathy
• Cardiovascular risk factors - may persist despite remission 1

The comprehensive evaluation and appropriate treatment of Cushing's syndrome are essential to reduce the significant morbidity and mortality associated with this condition, including cardiovascular complications, infections, and neuropsychiatric disorders.