Repeat Transsphenoidal Surgery Research Articles

Management of Recurrent and Refractory Cushing's Disease with Reoperation and/or Proton Radiosurgery

Aghi, Manish K. M.D., Ph.D.; Petit, Josh; Chapman, Paul; Loeffler, Jay; Klibanski, Anne; Biller, Beverly; Swearingen, Brooke

Outcomes and Management of Patients with Cushing’s Disease without Pathological Confirmation of Tumor Resection after Transsphenoidal Surgery

Despite the success of transsphenoidal surgery (TSS) for the treatment of Cushing's disease, in a number of cases, an ACTH-staining pituitary adenoma is not identified histologically. The clinical significance of lack of histological confirmation remains unclear. This was a retrospective review of patients treated at the University of Virginia Medical Center. Of 490 TSS procedures for Cushing's disease between 1993 and 2004, we identified 111 cases without histological adenoma confirmation. Remission and recurrence of Cushing's disease were measured. Overall, 50% of these patients achieved remission, a figure lower than for our entire series (79%) and for patients with histological confirmation of an ACTH-staining adenoma (88%) (P < 0.001). Patients with a history of two prior TSS achieved remission less often than patients with a history of fewer TSS (P = 0.026). No other factors influenced remission rates. Although the overall recurrence rate (21%, seven of 33 evaluated) was not different from previously published long-term studies, in three of seven cases of recurrence, early recurrences were noted between 2 and 4 months after remission. In patients who did not achieve remission, the most common and effective treatment options were repeat TSS, gamma-knife radiosurgery, and bilateral adrenalectomy. The lower remission rate in patients without histological evidence of an adenoma is most likely a result of a decreased rate of adenoma extirpation. The incidence of early recurrence may be a unique feature of this patient population; patients without histological confirmation of tumor resection therefore require close and consistent monitoring postoperatively.

Suboptimal Sphenoid and Sellar Exposure: A Common Theme in Patients Treated with Repeat Trans-sphenoidal Surgery for Residual Macroadenomas

Introduction: We assess possible reasons for prior subtotal removal, reoperative success, complication rates, and patient impressions in patients with residual endocrine-inactive macroadenomas.

Suboptimal Sphenoid and Sellar Exposure: A Consistent Finding in Patients Treated with Repeat Transsphenoidal Surgery for Residual Endocrine-inactive Macroadenomas

In a series of patients with residual endocrine-inactive macroadenomas who underwent repeat surgery, we assess possible reasons for prior subtotal removal, reoperative success, complication rates, and patient impressions. All patients were identified who had a prior subtotal removal of an endocrine-inactive macroadenoma and were reoperated on for residual sellar tumor via an endonasal approach. Over 6 years, of 188 consecutive patients with endocrine-inactive adenomas, 30 (16%) had repeat surgery (age, 15-77 yr; median interval between surgeries, 25 mo; median follow-up, 20 mo). Maximal tumor diameter averaged 2.4 +/- 0.9 cm. At reoperation, a suboptimal bony exposure was seen in all 30 patients: at the sphenoid keel, the sella, or both in 97, 93, and 90% of patients, respectively. Cavernous sinus invasion was seen in 16 (53%) patients and a fibrous/rubbery consistency in 12 (40%). Gross total tumor removal was achieved in 17 (57%) patients, including 12 of 14 (86%) with noninvasive tumors and 5 of 16 (31%) with invasive tumors, (P < 0.01). All six fibrous/rubbery but noninvasive tumors were totally removed. Of 16 patients with preoperative visual loss, 15 (94%) improved. Complications included one each of cerebrospinal fluid leak, delayed sinusitis, and new hypothyroidism. In 17 patients with prior sublabial surgery who completed questionnaires, the second (endonasal) surgery was associated with an easier recovery, less pain, and better nasal airflow in 82, 88, and 93%, respectively (P < 0.0001). In patients with residual sellar endocrine-inactive adenomas, a suboptimal opening at the sphenoid keel or sella at the first surgery and a high proportion of fibrous/rubbery tumors likely contributed to prior subtotal removal of otherwise accessible tumor. With a wider exposure, most noninvasive tumors can be totally removed, whereas invasive tumors can be effectively debulked. An endonasal reoperation is well tolerated with a low complication rate.

Clinical and endocrine responses to pituitary radiotherapy in pediatric Cushing's disease: an effective second-line treatment.

Transsphenoidal surgery (TSS) is considered first-line treatment for Cushing's disease (CD). Options for treatment of postoperative persisting hypercortisolemia are pituitary radiotherapy (RT), repeat TSS, or bilateral adrenalectomy. From 1983 to 2001, we treated 18 pediatric patients (age, 6.4-17.8 yr) with CD. All underwent TSS, and 11 were cured (postoperative serum cortisol, <50 nM). Seven (39%) had 0900-h serum cortisol of 269-900 nM during the immediate postoperative period (2-20 d), indicating lack of cure. These patients (6 males and 1 female; mean age, 12.8 yr; range, 6.4-17.8 yr; 4 prepubertal; 3 pubertal) received external beam RT to the pituitary gland, using a 6-MV linear accelerator, with a dose of 45 Gy in 25 fractions over 35 d. Until the RT became effective, hypercortisolemia was controlled with ketoconazole (dose, 200-600 mg/d) (n = 4) and metyrapone (750 mg-3 g/d) +/- aminoglutethimide (1 g/d) or o'p'DDD (mitotane, 3 mg/d) (n = 3). All patients were cured after pituitary RT. The mean interval from RT to cure (mean serum cortisol on 5-point day curve, <150 nM) was 0.94 yr (0.25-2.86 yr). Recovery of pituitary-adrenal function (mean cortisol, 150-300 nM) occurred at mean 1.16 yr (0.40-2.86 yr) post RT. At 2 yr post RT, puberty occurred early in one male patient (age, 9.8 yr) but was normal in the others. GH secretion was assessed at 0.6-2.5 yr post RT in all patients: six had GH deficiency (peak on glucagon/insulin provocation, <1.0-17.9 mU/liter) and received human GH replacement. Follow-up of pituitary function 7.6 and 9.5 yr post RT in two patients showed normal gonadotropin secretion and recovery of GH peak to 29.7 and 19.2 mU/liter. The seven patients were followed for mean 6.9 yr (1.4-12.0 yr), with no evidence of recurrence of CD. In conclusion, pituitary RT is an effective and relatively rapid-onset treatment for pediatric CD after failure of TSS. GH deficiency occurred in 86% patients. Long-term follow-up suggests some recovery of GH secretion and preservation of other anterior pituitary function.

Long-term outcome in children and adolescents after transsphenoidal surgery for Cushing's disease.

Cushing's disease refers specifically to an ACTH-producing pituitary adenoma that stimulates excess cortisol production. Transsphenoidal surgery is the treatment of choice in children and adolescents, but disparate cure rates have been reported, ranging from 50-98%. The discrepancies in cure rate are due primarily to the technical success of the surgery and the length and method of follow-up. We studied 42 consecutive children and adolescents (age, < or = 18 yr) who underwent transsphenoidal exploration for the primary treatment of Cushing's disease at University of California-San Francisco from 1974-1993. Only 7 patients had persistent disease, defined as evidence of Cushing's disease within 6 months of surgery, yielding an initial remission rate of 83%. We comprehensively evaluated 26 of the 35 patients who experienced an initial remission, including testing of the ACTH-adrenocortical axis. The mean duration of follow-up is 7.2 yr (range, 1.5-13.6 yr). Seven experienced a relapse of Cushing's disease, yielding a net remission rate of 73%. Relapses occurred an average of 4.2 yr postoperatively (range, 0.75-6.2 yr). Five patients experienced relapse within 5 yr of surgery, whereas 2 relapsed more than 5 yr postoperatively. Repeat transsphenoidal surgery was performed in 8 patients with persistent or recurrent disease, and 6 of these remain in remission. Low serum or urinary cortisol measurements within the first post-operative week predicted remission of Cushing's disease, but were not necessarily predictive of long-term cure. Hypercortisolism had significant effects on bone metabolism, as reflected by both diminished bone density in the majority of patients examined and decreased growth rate. Both parameters improved after surgical care, although they did not fully normalize. We conclude that transsphenoidal surgery is a safe and effective treatment for pediatric Cushing's disease, but long-term surveillance is necessary to detect possible recurrences.

Adrenocorticotrophic hormone-dependent Cushing's syndrome.

Excess endogenous glucocorticoid production, whether ACTH dependent or ACTH independent, results in the classic clinical and biochemical picture of Cushing's syndrome. The diagnosis requires the demonstration of an increased cortisol secretion rate, best achieved by using the 24-hour UFC corrected for body surface area as an index. In mild cases, distinction from the hypercortisolism of pseudo-Cushing states may be difficult. A dexamethasone/o CRH test or close monitoring of the patient for a few months may be helpful. A discrete pituitary lesion on imaging and a standard oCRH test with results consistent with such a lesion are sufficient to proceed to trans-sphenoidal surgery. If no visible pituitary adenoma is present or if the oCRH test is equivocal, bilateral simultaneous inferior petrosal sinus sampling with oCRH administration is necessary to distinguish between a pituitary and an ectopic source. Surgical ablation is the treatment of choice for all types of Cushing's syndrome. In the 5% of cases with Cushing's disease in whom trans-sphenoidal surgery fails and in the 5% of cases in whom the disease recurs, repeat trans-sphenoidal surgery or radiation therapy in association with mitotane treatment may be pursued. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the ACTH-secreting tumor is unsuccessful and radiation/medical therapy fails.

Differential diagnosis and management of Cushing's syndrome.

The diagnosis of endogenous Cushing's syndrome requires demonstration of an increased cortisol secretion rate, best achieved by urinary free cortisol excretion determinations. In borderline or confusing cases, loss of diurnal cortisol rhythmicity, a combined dexamethasone/corticotropin releasing hormone (CRH) test, or close monitoring of the patient for a few months will be helpful in ruling out pseudo-Cushing's. Primary adrenal Cushing's syndrome can be ruled out on the basis of a normal or elevated basal and/or CRH-stimulated plasma adrenocorticotropin (ACTH) and a negative adrenal computed tomography. ACTH-dependent Cushing's syndrome can then be differentiated on the basis of a CRH test and imaging procedures. A discrete pituitary lesion on magnetic resonance imaging and a standard CRH test with results consistent with such a lesion are sufficient to proceed to transsphenoidal surgery. If no discrete pituitary lesion is present, or if the CRH test is equivocal, bilateral simultaneous inferior petrosal sinus sampling with CRH administration is necessary to distinguish between a pituitary and an ectopic source. Surgery is the treatment of choice for all types of Cushing's syndrome. In the few cases in which transsphenoidal surgery fails or the disease recurs, repeat transsphenoidal surgery, or radiation therapy in association with mitotane treatment, is a reasonable alternative. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the ACTH-secreting tumor is unsuccessful and radiation/medical therapy fails.

Clinical presentation, diagnosis, and treatment of Cushingʼs syndrome

Excess endogenous glucocorticoid production, whether corticotropin-dependent or -independent, results in the classic clinical and biochemical picture of Cushing's syndrome. The diagnosis requires demonstration of an increased cortisol secretion rate, but in mild cases, distinction from the hypercortisolism of pseudo-Cushing states may prove difficult. A dexamethasone or ovine corticotropin-releasing hormone test or close monitoring of the patient for a few months may be helpful. Most cases are diagnosed using: corticotropin-releasing hormone—stimulated plasma corticotropin level measurements and adrenal imaging procedures, A discrete pituitary lesion on imaging and a standard ovine corticotropin-releasing hormone test with results consistent with such a lesion are sufficient to proceed to transsphenoidal surgery. If no visible pituitary lesion is present, or if the ovine corticotropin-releasing hormone test is equivocal, bilateral simultaneous inferior petrosal sinus sampling with ovine corticotropin-releasing hormone administration is necessary to distinguish between a pituitary and an ectopic source. Surgical ablation is the treatment of choice for all types of Cushing's syndrome. In cases in which transsphenoidal surgery fails or in which the disease recurs, repeat transsphenoidal surgery and radiation therapy in association with mitotane treatment are reasonable alternatives. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the corticotropin-secreting tumor is unsuccessful and radiation or medical therapy fails.

Advances in the diagnosis and treatment of Cushing's syndrome

Excess endogenous glucocorticoid production, whether ACTH-dependent or ACTH-independent, results in the classic clinical and biochemical picture of Cushing's syndrome. The diagnosis requires demonstration of an increased cortisol secretion rate, best achieved using determination of urinary free cortisol as an index. In mild cases, distinction from the hypercortisolism of pseudo-Cushing states may prove difficult. If the physician is in doubt, a dexamethasone/CRH test should be performed. Primary adrenal Cushing's syndrome can be diagnosed on the basis of undetectable plasma ACTH and the results of adrenal imaging procedures. ACTH-dependent Cushing's syndrome can be differentiated using an oCRH test and imaging procedures. In the presence of a discrete pituitary lesion on imaging, a standard oCRH test with results consistent with such a lesion is sufficient to proceed to transsphenoidal surgery. In the absence of such a lesion or if the oCRH test is equivocal, simultaneous BIPSS with oCRH administration should be performed to distinguish between a pituitary or ectopic source. Surgical ablation is the treatment of choice for all types of Cushing's syndrome. In the 5% of cases with Cushing's disease in whom transsphenoidal surgery fails and in the 5% of cases in whom the disease recurs, repeat transsphenoidal surgery or radiation therapy in association with mitotane treatment are reasonable alternatives. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the ACTH-secreting tumour is unsuccessful and radiation/medical therapy fails.

Early repeat surgery for persistent Cushing's disease.

The potential efficacy of early repeat transsphenoidal surgery for persistent Cushing's disease has not previously been examined. On 222 patients with no prior pituitary treatment and a preoperative diagnosis of Cushing's disease, 29 (13%) remained hypercortisolemic after an initial transsphenoidal pituitary exploration. Seventeen of these 29 patients underwent further surgery 7 to 46 days after the initial transsphenoidal approach in order to completely excise suspected residual tumor. Patients were followed for 4 to 84 months (mean +/- standard deviation, 34 +/- 25 months) to document sustained remission or recurrence of Cushing's disease (a urine free cortisol level > 90 micrograms/day was considered evidence of recurrence). Of the 17 patients with repeat surgery, 12 (71%) had resolution of hypercortisolism (morning plasma cortisol level < 5 micrograms/dl); however, in three of these 12, hypercortisolism recurred 5, 12, and 24 months later. In 14 patients a lesion that appeared to be a tumor was identified during the initial procedure or on histological examination. Of these, 12 had immediate resolution of hypercortisolism and nine are still in remission. Three patients, in whom no adenoma could be identified during the initial surgery or an examination of the partial hypophysectomy specimen from the initial surgery, had persistent Cushing's syndrome after the second operation. Seven (41%) of the 17 patients developed hypopituitarism requiring treatment with thyroid hormone, gonadal steroid, or vasopressin replacement. The low incidence of identification of an adenoma on computerized tomography or magnetic resonance images (three of 17 patients), the failure to find a corticotrophic adenoma during the initial surgery (10 of 17 patients), and the failure of these 17 patients to respond to the initial transsphenoidal surgery suggest that they may comprise a subset of patients who are more difficult to treat successfully with surgery than most patients with Cushing's disease. Despite that, early reoperation induced immediate remission of hypercortisolism in 71% of cases, but did so at the expense of a high risk of hypopituitarism. However, since the alternative treatments (such as radiation therapy, long-term drug therapy, or bilateral adrenalectomy) also have potential adverse effects, early reoperation deserves consideration for the management of persistent Cushing's disease, especially when an adrenocorticotrophic hormone-secreting adenoma was partially excised during the first surgery.

Transsphenoidal surgery following unsuccessful prior therapy. An assessment of benefits and risks in 158 patients.

The authors report the results of a retrospective study conducted in an effort to define the results and risks of transsphenoidal surgery for patients whose prior therapy had failed. In a series of 1210 patients undergoing transsphenoidal surgery during a 10-year period, 158 had received prior therapy: 127 for pituitary adenoma, 20 for craniopharyngioma, and 11 for other lesions. Prior therapy was considered "direct" when it consisted of craniotomy or transsphenoidal surgery (either open or stereotaxic), and "indirect" when it consisted of radiation therapy, adrenalectomy, or bromocriptine therapy. The current transsphenoidal operation was performed for persistent hyperfunctioning endocrinopathy in 63 patients, for visual loss in 72 patients, and for cerebrospinal fluid (CSF) rhinorrhea in 21 patients. Success rates were as follows: normalization of endocrinopathy was achieved in 35% of cases; improvement or stabilization of vision in 59%; and successful repair of CSF rhinorrhea in 74%. The risks associated with repeat transsphenoidal surgery are significantly greater than the same procedure in a previously untreated patient.