Transsphenoidal Surgery For Cushing's Disease Research Articles

A Combined Dexamethasone Desmopressin Test as an Early Marker of Postsurgical Recurrence in Cushing’s Disease

Recurrence of Cushing's disease (CD) after transsphenoidal surgery (TSS) occurs in about 25% of cases. Twenty percent of patients with immediate postsurgical corticotroph deficiency will present late recurrence. The aim of the study was to evaluate a coupled dexamethasone desmopressin test (CDDT) as a predictor of recurrence of CD. We conducted a prospective bicenter study (Marseille and Grenoble, France). We studied 38 patients treated by TSS for CD with a mean follow-up of 60 months. We evaluated 24-h urinary free cortisol, ACTH, and cortisol plasmatic levels and performed low-dose dexamethasone suppression test and CDDT 3 to 6 months after surgery and then yearly. After CDDT, ACTH ratio (ACTHr) was defined as (PeakACTH - BaseACTH)/BaseACTH. Cortisol ratio (Cortisolr) was defined as (PeakCortisol - BaseCortisol)/BaseCortisol. Basal values were observed after low-dose dexamethasone suppression test. Receiver operator characteristics curve defined ACTHr and Cortisolr giving the best sensitivity and specificity associated with recurrence. Ten patients presented recurrence. ACTHr and Cortisolr were superior or equal to 0.5 in all patients with recurrence and in three of 28 patients in remission (100% sensitivity, 89% specificity). The test became positive in eight of 10 patients with recurrence 6-60 months before classical markers of hypercortisolism. Six patients with immediate postsurgical corticotroph deficiency presented recurrence. All of them presented CDDT positivity during the 3 yr after surgery, and recurrence 6 to 60 months after CDDT positivity. CDDT is an early predictor of recurrence of CD and could be of particular interest in the first 3 yr after surgery, by selecting patients at high risk of recurrence despite falsely reassuring classical hormonal markers.

Midnight Salivary Cortisol Determination for Assessing the Outcome of Transsphenoidal Surgery in Cushing’s Disease

Midnight salivary cortisol (MSC) is now recognized as a reliable index for Cushing's syndrome diagnosis but has to be validated for the follow-up of treated patients. Our objective was to evaluate MSC for assessing the outcome of transsphenoidal surgery (TSS) in patients with Cushing's disease (CD). We conducted a retrospective cohort study in a single center. Sixty-eight patients treated by TSS between 1996 and 2006 and followed for at least 6 months with postoperative MSC were included. Mean follow-up (+/- sd) was 45 +/- 31 months. Morning plasma cortisol was determined 5 d after TSS, and MSC and urinary cortisol (UC) were determined 6-12 months after surgery. The remission group included hypocortisolic (morning plasma cortisol < 50 ng/ml and/or insufficient response to cosyntropin) and eucortisolic (midnight plasma cortisol < 75 ng/ml and normal UC) patients. Patients in the treatment failure group had high midnight plasma cortisol and UC concentrations. Fifty patients (74%) were in remission. Mean MSC was 0.7 +/- 0.4 ng/ml (range, 0.4-2.1 ng/ml) and 6.5 +/- 6.5 ng/ml (range, 2.1-27.2 ng/ml) for the remission and treatment failure groups, respectively (P = 0.001). A cutoff of 2 ng/ml for MSC gave a sensitivity of 100% and a specificity of 98% for treatment failure diagnosis, whereas UC less than 90 microg/d had a sensitivity of 71% and specificity of 98%. Postsurgical morning plasma cortisol less than or equal to 18 ng/ml had a sensitivity of 93% and specificity of 74%. MSC is a simple, robust marker of remission after TSS for CD.

Transsphenoidal surgery for Cushing disease: results of our experience in 39 consecutive patients

To evaluate magnetic resonance imaging (MRI) characteristics and surgical results of adrenocorticotropin (ACTH)-secreting pituitary adenomas.MRI characteristics and relationship between MRI positive rate and surgical results of 266 patients with pathologically confirmed Cushing's disease were analyzed retrospectively. All patients underwent thin-section sagittal and coronal scans of the pituitary gland before and after administration of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) on a 1.5 Tesla MRI scanner, and dynamic enhanced MRI was performed in 39 patients. All patients underwent transsphenoidal adenomectomy. Endocrinological examinations and assessments were performed.Preoperative MRI revealed normal results in 41 (15.4%) cases, microadenoma in 179 (67.3%), macroadenoma in 42 (15.8%), and huge adenoma in 4 (1.5%). Pituitary apoplexy was found in 13 (4.9%) cases. Positive rate of ACTH-secreting adenomas was 84.6% (225/266) on MRI scans, and that of small microadenomas was 87.2% (34/39) on dynamic enhanced MRI scans. Preoperative endocrinological tests of 199 cases supported the diagnosis of typical Cushing's disease, while the other 67 cases had atypical endocrinological results. The endocrinological cure rate, remission rate, and inefficacy rate were 85.7%, 7.9%, and 6.4%, respectively. There was no difference in the initial endocrinological cure rate between the patients with positive and normal MRI results (90% vs. 87.8%, P = 0.904).Enhanced coronal pituitary MRI is helpful for preoperative localization of ACTH-secreting pituitary microadenoma. Dynamic enhanced MRI may improve detection rate of microadenoma. There is no marked difference in the surgical results for patients with preoperative MRI results indicating presence or absence of microadenoma.

Early Postoperative Plasma Adrenocorticotropin as a Predictor of Cure of Cushing Disease

A plasma cortisol less than 50 nmol/L in the early postoperative stage after transsphenoidal surgery for Cushing disease has been proposed as predictive of cure. Data on postoperative plasma adrenocorticotropin (ACTH) are scarce. The objective of this study was to establish whether plasma ACTH, in the early postoperative period after transsphenoidal surgery for Cushing disease, can predict cure and how its prognostic value compares with that of plasma cortisol. We analyzed 13 patients with Cushing disease (mean age, 43 years) treated by transsphenoidal surgery. Serum cortisol and plasma ACTH samples were taken on the seventh day after surgery. Follow up was between 12 and 55 months (mean, 34 months). During this time, samples for basal serum cortisol and after stimulation with 250 μg ACTH1–24, basal plasma ACTH, 24-hour urinary-free cortisol, and plasma cortisol after an overnight dexamethasone suppression test were measured periodically to evaluate their clinical status. Twelve of the 13 patients were in remission during the follow-up period. The early postoperative serum cortisol level was 50 nmol/L or less in only 4 of the 12 patients in remission, whereas the plasma ACTH level was 2 pmol/L or less in 6 of these patients. Normal values for plasma ACTH were between 2 and 12 pmol/L. The value of plasma ACTH level measured in the first postoperative week is not a better predictor of cure than early postoperative serum cortisol level.

Transsphenoidal surgery in Cushing disease: 10 years of experience in 34 consecutive cases.

Cushing disease is a rare disorder. Because of their small size the adrenocorticotropic hormone (ACTH)-producing tumors are often not detectable on neuroimaging studies. To obtain a cure with transsphenoidal surgery (TSS) may therefore be difficult. In this report the authors present 10 years of experience in the treatment of patients with Cushing disease who were followed up with the same protocol and treated by the same surgeon. Thirty-four patients, 26 of them female and eight of them male (mean age 40 years, range 13-74 years) were studied. All had obvious clinical signs and symptoms of Cushing syndrome. Magnetic resonance (MR) imaging was performed in all patients, and inferior petrosal sinus (IPS) sampling was done in 14. In 12 patients MR imaging indicated a pituitary tumor; 10 were microadenomas and two were macroadenomas. In six patients with no visible tumor, the results of IPS sampling supported the diagnosis. All patients underwent TSS; the mean follow-up duration was 6 +/- 0.5 years. Selective adenomectomy was performed in 32 and hemihypophysectomy in the other two patients. A cure was obtained in 31 patients (91%) after one TSS and in two more patients after further TSS; one patient was not cured despite two TSSs and one underwent bilateral adrenalectomy. Disease recurrence was seen in two patients after 3 years, and they were successfully treated with stereotactic gamma knife surgery. Half of the patients had an ACTH deficiency postoperatively, whereas one third had other pituitary hormone insufficiencies. There were no serious complications attributable to the surgical intervention. Transsphenoidal surgery with selective adenomectomy is an effective and safe treatment for Cushing disease. In the patients presented in this study, the surgical outcome seemed to depend on careful preoperative evaluation and the surgeon's experience. For optimal results in this rare disease the authors therefore suggest that the endocrinological, radiological, and surgical procedures be coordinated in a specialized center.

Ectopic intracavernous sinus adrenocorticotropic hormone—secreting microadenoma: could this be a common cause of failed transsphenoidal surgery in Cushing disease?

Despite diagnostic advances, it remains difficult to identify intrasellar and ectopic parasellar adrenocorticotropic hormone (ACTH)-secreting microadenomas. The authors present the case of a 61-year-old woman with Cushing disease in whom a significant central-to-peripheral and lateralized right-sided ACTH gradient was demonstrated on inferior petrosal sinus sampling; no discernible abnormality was seen on magnetic resonance imaging. She underwent transnasal transsphenoidal surgery. No tumor was found on sellar exploration and a total hypophysectomy was performed, yet her hypercortisolemia persisted. The patient died of cardiac events 17 days postsurgery. Autopsy revealed an isolated, right-sided, intracavernous ACTH-secreting adenoma with no intrasellar communication. This case represents the first failed transsphenoidal surgery for Cushing disease in which there is postmortem confirmation of a suspected intracavernous sinus lesion. It supports the hypothesis that Cushing disease associated with nondiagnostic imaging studies, a strong ACTH gradient on venography, and negative findings on sellar exploration may be caused by an ectopic intracavernous ACTH-secreting adenoma. There are no premortem means of confirming the presence of such lesions, but these tumors could underlie similar cases of failed surgery. Radiation therapy targeting the sella turcica and both cavernous sinuses, possibly supplemented with medical treatment, is suggested for similar patients in whom transsphenoidal hypophysectomy has failed. Adrenalectomy may also be appropriate if a rapid reduction in ACTH is necessary.

Serum cortisol response to transsphenoidal surgery for Cushing disease.

Transsphenoidal surgery remains the optimal treatment for Cushing disease, but the definitions of surgical cure and failure remain debatable. In this study the authors evaluated serum cortisol levels in patients before and after they underwent transsphenoidal surgery to elucidate the patterns of cortisol decrease and the optimal time and criteria for determining surgically induced remission. Twenty-seven patients were evaluated throughout an 8-month period. Serum cortisol levels were obtained before surgery and at 6-hour intervals postoperatively. No exogenous steroid medications were administered until after cortisol sampling was discontinued, following diagnosis of remission. Twenty-one (78%) of 27 cases were labeled initial surgically induced remissions. Twenty-two (81%) of 27 cases were deemed surgically induced remissions at follow-up examination. Following surgery, initial remissions and failures demonstrated divergent patterns of cortisol levels. No patient whose condition was deemed an initial surgically induced remission has experienced definitive relapse of disease since discharge. One patient whose condition was initially deemed a surgical failure, eventually was found to exhibit surgically induced remission without further intervention. Given such findings, exogenous steroid medications do not appear to be required for patients until after the determination of remission. During the 1st postoperative day, there is a time period during which serum cortisol values significantly differ between the categories of surgically induced remissions and surgical failures. Surgically induced remissions were identified when postoperative values of cortisol were lower than preoperative midnight levels and when absolute values of cortisol were less than 10 microg/dl. In a small proportion of patients remission on a delayed basis may also be demonstrated. These data allow for a simple and rapid determination of postoperative remission in patients undergoing transsphenoidal surgery for Cushing disease.