Cushing’s Disease

CORTICOTROPIN (ACTH)-SECRETING PITUITARY TUMOR

Overview and Definition

• Excess Cortisol Production: Corticotropin (ACTH)-secreting pituitary adenomas stimulate excess adrenal secretion of cortisol, resulting in the clinical picture of Cushing syndrome.
• Typical Pathology:
  • Usually benign microadenomas (≤10 mm).
  • Occasionally macroadenomas, and very rarely carcinomas.

SURGICAL TREATMENT

Treatment of Choice

• Transsphenoidal Selective Adenectomy:
  • The definitive therapy for ACTH-secreting pituitary adenomas.
  • Surgical success is defined by cure of Cushing syndrome and intact anterior and posterior pituitary function.

Operative Approach

• Endonasal Route (often with endoscopy):
  • Via the sphenoid sinus (transsphenoidal approach) and through the floor of the sella.
• Histologic Findings:
  • Corticotroph adenomas are basophilic and stain positively for ACTH on immunohistochemistry.
  • Adjacent tissue often shows Crooke hyaline change, reflecting atrophy of normal corticotrophs.

Cure Rates and Challenges

• Success Rates:
  • 80% to 90% in cases where a microadenoma can be localized preoperatively by MRI or inferior petrosal sinus sampling.
• Reasons for Lack of Cure:
  1. Very small adenoma, not visualized at surgery.
  2. Inaccessible tumor location (e.g., involvement of the cavernous sinus).
• Macroadenomas:
  • Typically have a lower cure rate (~60%) due to cavernous sinus involvement preventing complete resection.

PREOPERATIVE AND INTRAOPERATIVE CONSIDERATIONS

Imaging

• High-Strength MRI (e.g., 3 tesla) with gadolinium enhancement:
  • Only about 50% of ACTH-secreting pituitary tumors are large enough to be detected by MRI.
  • ~10% of healthy individuals have an incidental small sellar lesion on MRI, which complicates specificity for a corticotroph adenoma in a patient with Cushing syndrome.

On the Day of Surgery

• Glucocorticoid Administration:
  • An intravenous dose of glucocorticoid (e.g., hydrocortisone, 100 mg) should be given.
• Monitoring Serum Cortisol:
  • Measure the morning serum cortisol concentration the day after surgery (before any additional exogenous glucocorticoid) to check for short-term cure (low serum cortisol, e.g., <1.8 μg/dL).
  • If acute glucocorticoid withdrawal symptoms occur before results are known, administer “stress dose” glucocorticoids (e.g., hydrocortisone 100 mg IV twice daily).

POSTOPERATIVE MANAGEMENT

Glucocorticoid Replacement and Taper

1. Initial Taper:
   • Reduce the steroid dose daily; most patients are discharged on about twice the standard glucocorticoid replacement (e.g., prednisone 10 mg in the morning and 5 mg at 4 pm daily).
   • Adjust dose based on severity of preoperative hypercortisolism to avoid severe steroid withdrawal.
2. Further Reduction:
   • Slowly taper to a standard replacement dosage over 4 to 6 weeks after the operation.
   • Patients typically transition to a single morning dose of a short-acting glucocorticoid (e.g., 15-20 mg hydrocortisone) starting 8 to 12 weeks post-cure.
3. Assessing Recovery of HPA Axis:
   • Measure 8 am serum cortisol every 6 weeks (before the morning dose of hydrocortisone).
   • Cortisol levels eventually rise from undetectable to >10 μg/dL. At that point, taper off the hydrocortisone over 2 weeks.
   • Most patients require exogenous glucocorticoids for approximately 12 months after curative surgery.
4. Resolution of Cushingoid Features:
   • Signs and symptoms related to Cushing syndrome improve very slowly over the first 6 months after surgery.

RECURRENCE AND LONG-TERM FOLLOW-UP

Risk of Recurrence

• Even with Low Postoperative Cortisol:
  • If any viable adenomatous corticotroph cells remain, they can multiply over time.
  • Average time to evident recurrence: 3 to 4 years.
• Annual Assessment:
  • All patients should have yearly follow-up to detect any return of hypercortisolism.

Thromboembolic Precautions

• Increased Thromboembolic Risk:
  • Patients with Cushing syndrome have a higher perioperative risk.
  • Early ambulation and prophylactic measures are encouraged.

ALTERNATIVE OR ADDITIONAL THERAPIES

When Surgery Fails or Is Incomplete

1. Repeat Transsphenoidal Surgery
2. Bilateral Laparoscopic Adrenalectomy
3. Radiation Therapy to the sellar region (less frequently used)
4. Pharmacotherapy to reduce adrenal cortisol production (also less common)