Selective transsphenoidal microadenomectomy, a procedure with a complete remission rate of nearly 95% on the first exploration (depending on the institution/ neurosurgeon) and the added advantage of producing eventually normal anterior pituitary function, is the initial therapy of choice for CD (4,86) (see Chapter 8).
Less than 10% of ACTH-secreting pituitary adenomas are macroadenomas. Only if these adenomas extend into the lateral parasellar and/or suprasellar regions is the transcranial approach used.
The neurosurgeon should always explore the entire pituitary gland to find the microadenoma responsible for the disease. If the adenoma is <5 mm, it may not be visible on the surface of the gland, but a vertical incision often will reveal it (87). If pituitary MRI did not identify an adenoma, cavernous sinus or inferior petrosal sinus sampling data (if presampling venography confirmed symmetric venous drainage and the lateralizing ACTH gradient is >2) may assist the neurosurgeon in lateralizing the adenoma during transsphenoidal exploration (88). The entire sellar region should be explored before any anterior pituitary tissue is removed. In patients with no identifiable tumor in situ at first sight, intraoperative ultrasound may be helpful (89). If an adenoma cannot be found during transsphenoidal exploration, the surgeon may perform a hemihypophysectomy on the site of a lateral IPS ACTH gradient >2. This approach has proved successful in approx 80% of cases (88,90). Few patients have extrapituitary parasellar microadenomas that probably arose from remnants of Rathke's pouch (88). Total hypophysectomy should not be performed in patients without identifiable adenoma during exploration, even if these patients do not insist on reproductive function. Failure of surgery at the first exploration may be followed by a repeat procedure with a 50-60% chance of complete remission (91). Success is defined as a drop of serum cortisol (8 AM) and/or urinary free cortisol to an undetectable level in the postoperative period (after d 2 postoperatively, off glucocorticoid administration) (92-94). A successful outcome can also be predicted by lack of cortisol or ACTH response to oCRH or desmopressin, when the test is performed 7-10 d after surgery (95,96).
In patients without histologically confirmed tumor (an abnormality/tissue that was removed in the belief it was the adenoma), complete remission occurs in 66% on an average follow-up of 38 mo (97).
Criteria to predict long-term remission are controversial and include undetectable serum cortisol, UFC, and ACTH levels in the (immediate) postoperative period and low-dose dexamethasone suppressibility and deficient responses with CRH and/or desmopressin stimulation 7-10 d after surgery (92-96,98,99). However, there are patients with long-term remission who had normal cortisol levels in the immediate postsurgical period (86,100). The lowest risk of relapse has been observed in patients who require prolonged glucocorticoid therapy after adenomectomy (101). A plasma cortisol <6^g/dL (166 nmol) and UFC <15^g/d (41 nmol) between postoperative d 3 and 5 can predict long-term remission (98). At our institution, patients are started on hydrocortisone replacement therapy on d 5 after surgery to treat secondary hypoadrenalism. Cosyntropin (Synacthen) stimulation testing is performed at three monthly intervals to assess recovery of the HPA axis.
The most common reason for residual disease is local invasion of the dura, especially of the lateral sellar wall, possibly with perforation of the sellar floor. The other major cause for surgical failure is the inability to localize the adenoma surgically (4,91).
Overall long-term remission rates for ACTH-secreting microadenomas range from 75% to 95%, depending on the institution and neurosurgeon (91,102). For macroadenomas, surgical long-term success is less than 70% because of frequent invasion of the dura, cavernous sinus, and adjacent structures. Repeat surgery does not significantly improve the outcome, making further therapies, including irradiation, medical therapy, and even bilateral adrenalectomy, necessary (91,103).
The complication rate of transsphenoidal surgery for the treatment of pituitary adenomas is low, with a perioperative mortality of less than 2% (major causes being: pulmonary embolism and myocardial infarction). Most frequently (<20% of patients), postoperative transient hyponatremia develops as part of the sydrome of inappropriate secretion of antidiuretic hormone (SIADH). Transient postoperative diabetes insipidus (<15% of patients) and CSF rhinorrhea (<5%) are also seen. Permanent diabetes insipidus develops in <3% of patients, usually in those who require more extensive surgery such as hemihypophysectomy or hypophy-sectomy. Meningitis is rarely seen and related to a CSF leak that usually is easily treated. Hypopituitarism occurs in less than 2% (4,80,101,104).
A second transsphenoidal operation may be indicated if CD persists and/or the first surgery was performed by an inexperienced surgeon (91). Providing that ectopic ACTH syndrome has been excluded, this surgery often involves a hemi-hypophysectomy or total hypophysectomy and only rarely a selective adenomectomy. If dura invasion was present at the first surgical exploration, no further transsphenoidal surgeries should be undertaken (except for debulking in rare cases), and radiation, medical therapy, and, in refractory cases, bilateral adrenalectomy should be employed.
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