What is the best management approach for Cushing disease?

Management of Cushing's Disease

Transsphenoidal surgery performed by an experienced pituitary surgeon is the first-line treatment for Cushing's disease, with the goal of removing the ACTH-secreting adenoma while preserving normal pituitary tissue. 1, 2

Diagnostic Approach

• Diagnosis requires multiple screening tests including late-night salivary cortisol (≥2 tests), 24-hour urinary free cortisol (2-3 collections), and/or dexamethasone suppression test 2
• Pituitary MRI should be performed to identify ACTH-secreting adenoma, though tumors may be small or not visible in many cases 2, 3
• Bilateral inferior petrosal sinus sampling (IPSS) is recommended to confirm pituitary source of ACTH when:
  • No lesion is visible on MRI 1
  • Lesions <6mm are detected on MRI 2
  • For lesions 6-9mm, expert opinions differ but majority recommend IPSS 2
  • For lesions ≥10mm with clinical/biochemical features consistent with Cushing's disease, IPSS is not necessary 2

Treatment Algorithm

First-Line Treatment

• Selective transsphenoidal adenomectomy by an experienced pituitary surgeon 2, 1
• Surgical success rates range from 70-90% when performed by experienced surgeons 4
• Early post-operative remission correlates with successful identification of adenoma during surgery, younger age, smaller adenoma size, and absence of cavernous sinus invasion 1

For Persistent or Recurrent Disease

1. Repeat transsphenoidal surgery

   • Consider when tumor remains visible on MRI 1
   • Remission rates of 50-70% for second surgery 4

2. Radiation therapy options

   • Stereotactic radiotherapy, fractionated proton beam therapy, or gamma knife radiosurgery 1
   • Remission occurs in ~85% of patients but with considerable latency period 4
   • Risk of developing hypopituitarism after radiation therapy 4

3. Medical therapy

   • Used while awaiting effects of definitive treatment or as adjunctive therapy 2
   • Options include:
     • Steroidogenesis inhibitors (metyrapone, ketoconazole) 2, 1
     • Pituitary-directed therapies (pasireotide) 2
     • Glucocorticoid receptor antagonists 2

4. Bilateral adrenalectomy

   • Consider for severe refractory disease or when rapid control of hypercortisolism is needed 5
   • Provides definitive control of hypercortisolism but requires lifelong adrenal hormone replacement 4
   • Risk of developing Nelson syndrome (progressive enlargement of pituitary tumor) 4

Management of Complications

• Thromboprophylaxis is recommended, especially perioperatively, as hypercoagulability persists even after cortisol normalization 2
• Risk of venous thromboembolism is 10-fold higher compared to patients with non-functioning adenomas 2
• Address comorbidities (hypertension, diabetes, dyslipidemia) concurrently with Cushing's disease treatment 2

Long-term Follow-up

• Lifelong monitoring is essential as recurrence can occur up to 15 years after apparent surgical cure 1
• Monitor for development of hypopituitarism following surgery or radiotherapy 1
• Evaluate for growth hormone deficiency 3-6 months postoperatively in patients who have not completed linear growth 1

Common Pitfalls

• Failure to recognize subclinical Cushing syndrome, which is the most common hormonal dysfunction caused by adrenal incidentalomas 2
• Inadequate perioperative management of comorbidities such as diabetes and hypertension 2
• Insufficient thromboprophylaxis, especially in the postoperative period 2
• Premature discontinuation of follow-up, as recurrence can occur many years after initial treatment 1