| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan (G.D.H.), Ann Arbor, Michigan 48109-0678; Department of Medicine, Division of Endocrinology and Metabolism (J.B.T.), and Department of Neurological Surgery (K.R.L., C.B.A., E.T.H, S.B., C.B.W.), University of California, San Francisco, California 94143; Department of Emergency Medicine, University of Texas Southwestern Medical Center (R.R.), Dallas, Texas 75390; and Department of Internal Medicine, Beth Israel Deaconess Medical Center (A.L.), Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Dr. Gary D. Hammer, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan, 5560 MSRB-II, Box 0678, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail: ghammer{at}umich.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Inclusion and exclusion criteria
The records of all patients undergoing surgery between February 1975 and March 1998 were reviewed. During this time period, patients with ACTH-secreting adenomas accounted for approximately 17% of those patients undergoing transsphenoidal surgery at UCSF, including those less than 18 yr of age and those with Nelson’s syndrome (C. B. Wilson, unpublished observations). The diagnosis of Cushing’s disease was based on the patient’s history, characteristic physical exam findings, laboratory data, magnetic resonance imaging (since 1985), selective venous sampling for ACTH, surgical findings, and histopathology. Immunohistochemistry using antibodies to ACTH was routinely performed on surgical specimens since 1987.
Patients were excluded from the study if they were younger than 18 yr of age at the time of the surgery, had undergone previous pituitary or adrenal surgery, or had Nelson’s syndrome.
Surgical procedure, tumor classification, and postoperative endocrine evaluation
All operations were performed by one surgeon (C.B.W.) as previously described (10, 11, 12). If the surgeon was unable to localize and selectively resect an adenoma, in almost all cases he elected to perform total, hemi-, or partial hypophysectomy or to perform a biopsy. In each case, the primary aim at surgery was exploration of the entire sellar contents and selective removal of an adenoma when possible. In a few cases, if the tumor margin was indistinct, the surgeon removed 2–3 mm of normal adjacent anterior lobe, and the procedure was termed partial hypophysectomy. If the surgeon encountered tissue that appeared abnormal but was not typical of an adenoma, then he performed biopsy only. In the era before magnetic resonance imaging and central venous sampling for ACTH, if no adenoma could be identified, then, with the patient’s prior informed consent, total hypophysectomy was performed. In subsequent patients, if no tumor was identified, then hemihypophysectomy was performed in those who had undergone central venous sampling with lateralization to one lobe of the anterior pituitary. If the patient had not consented to total or hemihypophysectomy, the procedure was terminated and was classed as a negative exploration. These decisions regarding the type of procedures performed were made by the surgeon based on his intraoperative findings and not on the basis of pathological results. Tumors were classified by neuroradiographic and intraoperative findings as to the size, degree of sellar destruction (grade), and suprasellar extension (stage) (11, 13).
In the majority of patients, basal or dexamethasone-suppressed plasma and/or urinary cortisol levels were measured postoperatively, within the first week after surgery, either in the hospital or, more recently, as an out-patient after discharge. If data in the immediate postoperative interval were not available, then subsequent laboratory data from UCSF or from referring physicians obtained within the first 6 months after surgery were used to classify the patient as having remission or persistent disease. If no laboratory data within the first 6 months were available for review or if pre- or postoperative data were insufficient to establish either the initial diagnosis or the postoperative remission/persistence status (see Definitions below), then patients were excluded from the study.
Data collection and patient follow-up
Data were recorded on standard forms for subsequent computer entry, and each form was reviewed for accuracy by one nurse (C.B.A.) and one physician (J.B.T.). The study and the consent process were approved by the committee on human research at UCSF. Data regarding the preoperative diagnosis, surgical procedure and findings, and immediate surgical outcome were obtained by review of hospital and departmental medical records and the records of referring and consulting physicians. These same sources were also reviewed for information on long-term follow-up.
We attempted to contact all patients living in the United States to obtain current clinical information by telephone interview. If a current address was not available, we attempted to locate the patient by using multiple search techniques, including contacting relatives and referring physicians. Information was obtained regarding the clinical status of all patients contacted, including the presence or absence of Cushingoid features and symptoms (moon facies, weakness, amenorrhea, weight gain, headache, hypertension, emotional lability, hirsutism, osteoporosis, and visual field disturbances). Current medical therapy and any intervening therapies, such as any additional operations or radiation therapy, were recorded. All patients were asked if they had taken hormone replacement medications and if they had experienced symptoms of either anterior pituitary dysfunction or recurrent Cushing’s disease at any point after surgery.
At the time of contact, patients were asked if they had a recent laboratory evaluation regarding Cushing’s disease. If so, these data were obtained from the patient or his/her physician. In addition, each patient contacted was asked to undergo an overnight 1-mg dexamethasone suppression test, with the plasma cortisol level determined at a local laboratory.
For follow-up regarding survival and mortality, if we were unable to contact the patients, then we used information from medical records, referring physicians, family members, and friends to determine whether the patient had died and the date of death. We also conducted a search using national databases to determine whether the patient had died or to define the most recent date the patient was known to be alive.
Definitions
Patients were considered to be in initial postoperative remission if they had a basal or dexamethasone-suppressed plasma cortisol level of 5 µg/dl or less (
140 nmol/liter) determined within the first week after surgery. This level of plasma cortisol after 1 mg dexamethasone was chosen because it was the accepted normative value at the time of initiation of this surgical series. Patients for whom no immediate postoperative cortisol levels were available but who, within 6 months after surgery, had low or normal plasma or urinary cortisol, resolution of their clinical features, and no additional therapy were also considered to be in initial remission. Patients who had elevated postoperative cortisol levels and those who underwent additional therapy of Cushing’s disease within 6 months were defined as having persistent disease.
Patients who underwent bilateral adrenalectomy after surgery were classified as having persisting or recurrent disease as of the date of that surgery. We did not attempt to obtain additional laboratory follow-up for these patients, because laboratory data after adrenalectomy is not reliable. However, these patients were included in the survival analyses.
Patients were defined as being in long-term remission if 6 months post surgery they had follow-up information consistent with continued clinical remission, if they had a plasma cortisol after a 1-mg dexamethasone test of 5 µg/dl or less (140 nmol/liter) or a normal 24-h urinary free cortisol level at last follow-up, and if they had not undergone additional therapy. Three patients who were initially classified as having persistent disease had no additional therapy and had resolution of their clinical features (follow-up times of 4.2, 9.2, and 11.4 yr). These patients had dexamethasone-suppressed cortisol values of less than 2 µg/dl (56 nmol/liter), less than 0.2 µg/dl (5.6 nmol/liter), and less than 0.4 µg/dl (11.2 nmol/liter), respectively, and they were, therefore, classed as being in remission at the latest follow-up. A recurrence was defined as an initial remission followed by recurrent hypercortisolism or additional therapy 6 months or more post surgery. Time to recurrence was defined as the earlier of recurrent hypercortisolism or an additional therapy.
Major complications were defined as death within 30 d of surgery, significant hemorrhage, serious visual impairment, permanent hypopituitarism, cerebrospinal fluid (CSF) leak requiring surgical repair, and meningitis. Minor complications were defined as CSF leaks not requiring surgical repair.
Statistical analysis
Logistic regression analyses were performed on the variables tumor size, tumor stage, tumor grade, sex, and age to identify predictors of initial remission or persistence. This was done both for each variable individually and also using a backward multivariate stepwise procedure.
Expected mortality rates by age and sex, divided into 5-yr age groups, were obtained from the U.S. Bureau of Census (14) and compared with those observed in this study. The expected mortality rates for patients in this study were determined based on person-years of follow-up for each sex and age group. The difference between observed and expected rates was tested using the exact probabilities of the Poisson distribution (15).
Kaplan-Meier analysis (16) was used to estimate the probability of freedom from recurrence for patients in initial remission and to estimate survival curves for both the patients in remission and those with persistent disease based on the initial postoperative outcome. Expected survival curves were generated based on standard life-table methods using the expected mortality rates (14).
Statistical significance is defined as P 0.05 using a two-tailed test.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Patient population. Our study cohort included 289 patients who underwent transsphenoidal surgery from February 1975 to March 1998. We excluded 53 patients who were less than age 18 yr, 38 patients with Nelson’s syndrome, and four who had undergone prior transsphenoidal surgery. Three patients who had negative exploration were excluded because insufficient data were available to establish the diagnosis. In one patient no records were available; in the other two, preoperative endocrine data were equivocal, and postoperative follow-up suggested that they had pseudo-Cushing’s (depression in one and alcoholism in the other). An additional 13 patients were excluded because we could not obtain data to establish whether they were in postoperative remission or had persisting disease. These patients had preoperative laboratory data consistent with Cushing’s disease, and 11 of 13 had positive pituitary pathology confirming the diagnosis.
The median age of our 289 patients at the time of surgery was 37 yr (range, 18–72 yr). There were 239 (83%) female and 50 (17%) male patients. Radiation therapy had been administered to eight patients before surgery.
Tumor classification.
The median tumor size in 233 patients for whom we had data were 6 mm (mean, 7.5 mm; range, 1–30 mm). Grade and stage were described for 200 patients, and the majority of patients had tumors that were confined to the sella turcica without bony erosion of the sella floor (grade I or II; 96%). In addition, the majority of these adenomas did not have suprasellar extension or invasion of the cavernous sinus (stage 0; 68%). However, there were eight cases of localized perforation of the sellar floor (grade III; 4%) and 34 (17%) cases of cavernous sinus extension (stage E; 17%). No tumors exhibited destruction of the sellar floor (grade IV) or metastatic spread (grade V; Table 1
).
|
).
The majority of patients (227 of 289, 79%) underwent selective removal of the pituitary adenoma (Table 2). In 21% (62 of 289) of patients, no focal tumor was identified by the surgeon, and these patients underwent hemi- (or partial) hypophysectomy (25 of 289, 8.7%) or total hypophysectomy (23 of 289, 8.0%; see Patients and Methods). A small number of patients underwent negative pituitary exploration only (four of 289, 1.4%) or biopsy only (10 of 289, 3.5%).
|
). Remission was achieved in 83% (189 of 227) of those who underwent selective adenoma resection and in 85% (41 of 48) of those who underwent partial or total hypophysectomy. Only 43% (six of 14) of patients with exploration only or biopsy only achieved remission. A total of 253 of 289 (87.5%) patients had pathological confirmation of Cushing’s disease (pituitary ACTH hypersecretion). Of these, 249 patients were diagnosed as having pituitary adenoma based on histology and/or positive immunostaining for ACTH. Four patients had a pathological diagnosis of corticotrope hyperplasia. Remission was achieved in 211 of 253 (83.3%) of these patients with pathological confirmation of the diagnosis, and 42 of 253 (16.6%) had persisting disease. Thirty-six patients (36 of 289; 12.5%) had negative pathology, and after surgery 25 of 36 (69.4%) of these patients were in remission, and 11 of 36 (30.6%) had persisting disease.
Surgical remission was analyzed with reference to tumor classification (Table 1). In patients with grade I and II, adenomas (i.e. micro- and macroadenomas confined to the sella turcica) remission was achieved in 86% and 83%, respectively. However, if the tumor had perforated the floor of the sella turcica (grade III), only 63% of patients had initial remission. Patients with no suprasellar tumor extension (stage 0) or moderate suprasellar extension (stage A or B) had good surgical outcomes, with initial remission achieved in 88%, 94%, and 100%, respectively. However, if at surgery there was tumor extension into the cavernous sinus (stage E), initial remission occurred in only 65%. Thus, patients with adenomas confined to the sella turcica or with moderate suprasellar extension had the best surgical results.
Thirty-one of the patients with persistent disease had subsequent therapy within the first 6 months postoperatively. Nineteen patients underwent radiation therapy alone (including one who underwent 
-knife radiosurgery), five underwent bilateral adrenalectomy, and six underwent repeat transsphenoidal resection. One additional patient underwent repeat transsphenoidal resection and adrenalectomy. The subsequent outcome of these patients is discussed below.
Predictors of initial outcome. We examined whether gender, tumor size, grade, stage, or patient age would be predictive of the initial patient outcome using logistic regression. Based on logistic regression, male gender (P = 0.002), larger tumor size (P = 0.046), and higher stage (P = 0.003) predicted poorer outcomes. Using a multivariate logistic model with backward selection and a criterion of P < 0.05, male gender and higher stage remained in the model (P = 0.03 and P = 0.002, respectively). Because the analysis that included tumor size was limited by the number for whom tumor size was available, a final analysis was run including only gender and stage with an increased number of patients. This analysis found that higher tumor stage was statistically significant (P = 0.003), and gender was marginally significant (P = 0.09; data not shown).
Initial surgical morbidity and mortality.
There were three deaths within 30 d of surgery in three female patients, aged 50, 54, and 60 yr. These patients died 8, 9, and 20 d after operation, and in each case the cause of death was myocardial infarction and/or cardiac failure. One other 42-yr-old female patient died of cardiac arrest 2.5 months after surgery. An additional 14 patients had 19 postoperative surgical complications; of these, nine were major complications, including three cases of CSF leak requiring surgical repair and two cases each of meningitis, hematoma or hemorrhage, and permanent visual loss. There were nine cases of permanent diabetes insipidus and 25 patients with hypopituitarism (including the 23 patients who underwent total hypophysectomy; Table 3).
|
Patient follow-up.
Of the original 289 patients, follow-up for assessment of remission status after 6 months was obtained for 178, with a median follow-up time of 11.1 yr (range, 0.6–24.1 yr). Of these patients, 145 were followed for 5 yr, and 99 were followed for 10 yr or more (Table 4). Compared with patients in whom no long-term follow-up was available, patients who were followed beyond 6 months showed no significant difference in the clinical characteristics of gender, age, tumor size, grade, or stage (Table 5). Thus, there is no indication that patients with follow-up are a biased sample.
|
|
, of the 236 patients who were initially in remission, we had information more than 6 months post surgery for 150, and we were able to contact 139. Of the 150 patients, 137 were still in remission at the latest follow-up. These patients were considered to be in long-term remission only if they had continued clinical remission, normal values for dexamethasone suppression or 24-h urinary free cortisol, and had undergone no additional therapy (see Definitions). The median follow-up for those still in remission was 11.3 yr (range, 0.6–24 yr), and 75% of the patients had been followed for more than 6 yr. An additional 13 patients (13 of 150, 9%) had recurrent disease after 6 months. The median time to recurrence for these patients was 4.9 yr (range, 1.1–11.1 yr). Kaplan-Meier estimates for the probability for being relapse free were calculated, because this method adjusts for differential length of follow-up. These estimates were 95%, 91%, and 89% relapse free at 5, 10, and 15 yr post surgery. Twelve patients with recurrent Cushing’s disease underwent the following additional procedures: seven patients underwent an additional transsphenoidal resection, three patients underwent radiation therapy, and one patient underwent adrenalectomy. One patient underwent transsphenoidal resection and adrenalectomy. One patient with recurrent disease had not undergone additional therapy at the last follow-up. At their last follow-up, 11 patients were in remission, and two patients still had active disease.
|
). Of the 53 patients who displayed initial failure, we had long-term follow-up information for 28 patients and were able to contact 22. The median follow-up of these patients was 10 yr (range, 0.6–18.6 yr). In addition to the 31 patients who had undergone additional procedures within the first 6 months, 10 patients (including five who had also had procedures within 6 months) underwent additional therapies after 6 months. These included additional transsphenoidal surgery in three patients, transsphenoidal surgery and radiation in two patients, and transsphenoidal surgery plus adrenalectomy in one patient. Two patients underwent radiation therapy alone, and an additional two underwent adrenalectomy alone. At last follow-up, five of these patients were in remission, and five continued to have persistent disease. Ultimately, 18 of 28 patients were in remission at last follow-up, and 10 had persistent disease.
|
. The mean time from initial transsphenoidal resection to dexamethasone suppression testing was 12.36 yr. Of these 113 patients, 110 (97%) had postdexamethasone cortisol values of 5 µg/dl or less (140 nmol/liter), and 97 patients (86%) had cortisol values of 2 µg/dl or less (56 nmol/liter). None of the 13 patients with cortisol values between 3–5 µg/dl (84–140 nmol/liter) had clinical evidence of recurrence, and they were presumed to be in remission. The three patients with postdexamethasone morning cortisol values greater than 5 µg/dl (>140 nmol/liter) underwent additional evaluation with 24-h urinary cortisol measurement, and these results were normal in each case, confirming remission. Six of the 13 patients who had had recurrent disease were also tested (Table 6B). Five of these patients had postdexamethasone cortisol values of 5 µg/dl or less (140 nmol/liter) after additional therapy and were also in clinical remission at latest follow-up. The patient with the cortisol value of 26 µg/dl (728 nmol/liter) also had clinical symptoms and features of recurrent hypercortisolism (Table 6B). The overnight 1-mg dexamethasone suppression test was also performed in 17 of the 28 patients with follow-up of persistent disease (Table 6C). Of these, 14 had postdexamethasone cortisol values of 5 µg/dl or less (140 nmol/liter) and were also in clinical remission at last follow-up. Three patients continued to have persistent disease, with postdexamethasone cortisol values of 10–11 µg/dl (280–308 nmol/liter; Table 6C).
|
. There were a total of 29 deaths in the entire series. As stated above, four patients died within 6 months of their initial procedure (three within 30 d and one at 2.5 months). An additional 25 patients died after 6 months (one patient of these 29 was excluded from the survival analyses because the exact date of death could not be determined). Of the 29 patients who died, 23 were female, and six were male.
|
Initial assessment of the survival difference between groups (initial remission vs. initial persistent disease) by log-rank test was not statistically significant (P = 0.06; Table 8). We also evaluated the probability of death for patients in each group compared with the number of deaths expected based on age- and sex-matched population survival statistics. Of the 236 patients who were in initial remission after surgery, 17 had died, and this cumulative observed mortality rate did not differ significantly from the expected rate (P = 0.28; Fig. 3A and Table 9). Of the 53 patients with initial persistent disease after surgery, seven patients ultimately died. In contrast to the patients with initial remission, the group with initial persistent disease had a statistically significant increase in mortality in males (P = 0.05) and combined males and females (P = 0.01) compared with expected mortality (Fig. 3B and Table 9).
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Our study confirms that transsphenoidal resection is a safe procedure for patients with Cushing’s disease, with a low overall mortality rate similar to previous reports by us (9) and others (21, 22). The major complication rate of 3.1% in our study is nearly the same as in other reports in the literature. In prior studies, surgical, histopathological, and/or radiographic identification of tumors have all proven to predict good outcome compared with negative diagnostic identification (19, 21, 23, 24). This is logical in that if a tumor can be localized, there is a better chance of cure. However, as shown in our prior report (9) and more recent studies (23), larger, invasive and more aggressive tumors were associated with worse outcomes. In this series, higher tumor stage was the strongest predictor of poor surgical outcome (P < 0.01). These patients had stage E tumors, with invasion of the cavernous sinus precluding complete surgical resection.
The definition of a biochemical cure of Cushing’s disease has been the subject of much controversy (18, 23, 25), and a subset of patients can recur or relapse after presumed prior cure. As such, a successful outcome after treatment is perhaps better described as a remission. Predicting which patients are at risk for recurrence/relapse is therefore quite important. The immediate postoperative assessment of adrenal function is proving to be highly predictive of long-term outcome. Although low to undetectable cortisol levels postoperatively have been reported to predict a recurrence rate of 4.3%, normal or frankly high levels of cortisol postoperatively result in a 26.3% rate of recurrence (24, 26). In our experience, 82% of patients (236 of 289) had low cortisol levels within the first 6 months postoperatively, had no known additional procedures during that interval, and were considered in initial remission. This is similar to other studies that defined initial success rates as a suppressed cortisol measurement (20, 21, 24). Furthermore, the initial outcome data are consistent with our prior studies (9) and similar or better than other smaller series showing early remission rates between 70–90% (22, 27, 28). Eighteen percent of patients (53 of 289) in this study were not cured postoperatively, as manifested in a nonsuppressed cortisol level or an additional procedure within the first 6 months of surgery. Many of these patients underwent early reoperation or radiotherapy, similar to the experience of Trainer et al. (29).
Of the 150 patients in initial remission at 6 months for whom we had more than 6 month follow-up regarding remission status, 13 (9%) recurred some time during the course of follow-up. With so few recurrences, no risk factors could be associated with recurrence in these patients. These data do not agree with the high recurrence rates of 13–26% reported by others (18, 19, 24, 30), but are similar to those reported by Swearingen et al. (7) (7% at 10 yr compared with a 9% rate estimated in this report) and are similar to the rate reported in our smaller series (9) (5% mean 3.9 yr follow-up). The current series includes follow-up times of over 15 yr, and the risk of recurrence does not appear to be substantially higher after 10 yr, with a 15 yr estimated risk of 11%. Importantly, in patients with initial remission, even with recurrent disease, ultimate long-term remission is likely, with a final prevalence of active disease at final follow-up of 1.3% (two of 150 patients with initial remission with long-term follow-up data available for review). However, patients with initial persistent disease had less successful outcomes, as evidenced by both a higher prevalence of persistent disease at final follow-up (36%; 10 of 28 patients with initial persistent disease with long-term follow-up data) and an increased overall mortality.
The 1-mg overnight dexamethasone suppression test is a simple screening test for Cushing’s syndrome (31). The appropriate level of suppression is debated; however, patients with Cushing’s syndrome usually fail to suppress to 3.6–7.2 µg/dl (100–200 nmol/liter) (32, 33). A cut-off value of 3.6 µg/dl (100 nmol/liter) is highly sensitive, with a false negative rate as low as 2% (34). Suppression to less than 1.8 µg/dl (50 nmol/liter) is highly specific and virtually excludes Cushing’s syndrome (35), as discussed in a recent Cushing’s disease consensus statement (36). Using 5 µg/dl or less (140 nmol/liter) as our cut-off for normal, we used the test as a screening tool to assess the presence of persistent/recurrent Cushing’s disease with the test performed in local clinical laboratories. However, the results highlight the risk of false positive tests inherent with such a screening tool. If persistence or recurrence is suspected on the basis of the 1-mg dexamethasone suppression test, confirmatory testing should be performed with 24-h urinary free cortisol or late night salivary cortisol measurements.
There was no indication that survival in our patients with initial remission was different from that of the normal population (adjusted for age and sex). Our survival data at 5 yr (99%) and 10 yr (96%) for patients in initial remission were comparable to the 5 yr (99%) and 10 yr (93%) data reported for patients in initial remission by Swearingen et al. (7). Our report extends these studies and indicates prolonged preservation of survival at 15 yr in patients with initial remission of disease. In addition, our study indicates that patients with initial persistent disease have excess mortality compared with those in initial remission and to the population at large. The assessment of survival for this study was limited by the fact that we were not able to ascertain current survival status for all patients and had information on post-6-month survival for only 87% of our patients who lived more than 6 months postsurgery. However, because we used national databases, that allowed searches based on social security number and provided information on death, it is likely that our estimates of survival, if biased, would be biased toward shorter survival, because if a patient died, we would have been likely to find this out, whereas we considered the follow-up for the surviving patients to have ended at the date they were last known to be alive, which could be a substantial underestimate of the time they had survived after surgery. This strengthens the argument that survival for those in initial remission is not less than would be predicted in a normal population. It does imply that we may be overestimating the effect of persistent disease in increasing mortality. However, if we assume that all patients not known to be dead were alive at least to January 2000, the pattern of results remains unchanged (albeit without as strong a statistical statement; P = 0.05), and the conclusions remain consistent.
Only two modern series have addressed the issue of mortality in Cushing’s disease. In 1994, Etxabe and Vazquez (1) described continued excess mortality in a study of 49 patients. However, their data are not directly comparable, because their patients received multiple therapies (i.e. only 28 of 41 underwent transsphenoidal surgery as the initial procedure, 18 of 41 underwent bilateral adrenalectomy, and 16 of 41 underwent radiotherapy). In addition, it appears that eight of 49 (16%) of their patients did not undergo treatment. In contrast, Swearingen et al. (7) in 1999 reported normal survival in 161 patients initially treated by transsphenoidal surgery, followed by early repeat transsphenoidal surgery, adrenalectomy, and/or radiotherapy in those patients with persisting disease or recurrence. The researchers (7) did not find increased mortality in their patients with persisting disease; however, none of their patients had persisting cortisol excess at the time of last follow-up. However, in our series, 10 of 28 (36%) patients classified initially as having persisting disease and followed for more than 6 months had persisting hypercortisolism at the most recent follow-up. These differences suggest that early intervention to correct cortisol excess may reverse the excess mortality that we observed in our patients with persisting disease.
In conclusion, our results with a large series of patients confirm that initial remission can be achieved in approximately 80% of patients with Cushing’s disease. In those patients with initial remission, our recurrence rate was low, and survival appears to normalize in those patients who achieved initial remission. However, patients who had initial persistent disease had excess mortality. Our results, therefore, suggest that although patients in initial remission after transsphenoidal microsurgery appear to have normal survival, patients with persisting disease require early and aggressive therapeutic intervention to attempt to prevent excess mortality.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviation: CSF, Cerebrospinal fluid.
Received December 23, 2003.
Accepted September 12, 2004.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  D. L. Batista, E. H. Oldfield, M. F. Keil, and C. A. Stratakis Postoperative Testing to Predict Recurrent Cushing Disease in Children J. Clin. Endocrinol. Metab., August 1, 2009; 94(8): 2757 - 2765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Castinetti, M. Martinie, I. Morange, H. Dufour, N. Sturm, J.-G. Passagia, B. Conte-Devolx, O. Chabre, and T. Brue A Combined Dexamethasone Desmopressin Test as an Early Marker of Postsurgical Recurrence in Cushing's Disease J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 1897 - 1903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Trulea, M. Patey, B. Chaufour-Higel, F. Bouquigny, A. Longuebray, P. Rousseaux, C. Pasqual, A. Tabarin, and B. Delemer An Unusual Case of Ectopic Adrenocorticotropin Secretion J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 384 - 385. [Full Text] [PDF]
|
|
|
|
|
|
C. A. Carrasco, J. Coste, L. Guignat, L. Groussin, M. A. Dugue, S. Gaillard, X. Bertagna, and J. Bertherat Midnight Salivary Cortisol Determination for Assessing the Outcome of Transsphenoidal Surgery in Cushing's Disease J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4728 - 4734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. K. Biller, A. B. Grossman, P. M. Stewart, S. Melmed, X. Bertagna, J. Bertherat, M. Buchfelder, A. Colao, A. R. Hermus, L. J. Hofland, et al. Treatment of Adrenocorticotropin-Dependent Cushing's Syndrome: A Consensus Statement J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2454 - 2462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Petit, B. M. K. Biller, T. I. Yock, B. Swearingen, J. J. Coen, P. Chapman, M. Ancukiewicz, M. Bussiere, A. Klibanski, and J. S. Loeffler Proton Stereotactic Radiotherapy for Persistent Adrenocorticotropin-Producing Adenomas J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 393 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. G. Patil, D. M. Prevedello, S. P. Lad, M. L. Vance, M. O. Thorner, L. Katznelson, and E. R. Laws Jr. Late Recurrences of Cushing's Disease after Initial Successful Transsphenoidal Surgery J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 358 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Pouratian, D. M. Prevedello, J. Jagannathan, M. B. Lopes, M. L. Vance, and E. R. Laws Jr. Outcomes and Management of Patients with Cushing's Disease without Pathological Confirmation of Tumor Resection after Transsphenoidal Surgery J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3383 - 3388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. M. Dekkers, N. R. Biermasz, A. M. Pereira, F. Roelfsema, M. O. van Aken, J. H. C. Voormolen, and J. A. Romijn Mortality in Patients Treated for Cushing's Disease Is Increased, Compared with Patients Treated for Nonfunctioning Pituitary Macroadenoma J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 976 - 981. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R M Testa, N Albiger, G Occhi, F Sanguin, M Scanarini, S Berlucchi, M P Gardiman, C Carollo, F Mantero, and C Scaroni The usefulness of combined biochemical tests in the diagnosis of Cushing's disease with negative pituitary magnetic resonance imaging Eur. J. Endocrinol., February 1, 2007; 156(2): 241 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F Castinetti, M Nagai, H Dufour, J-M Kuhn, I Morange, P Jaquet, B Conte-Devolx, J Regis, and T Brue Gamma knife radiosurgery is a successful adjunctive treatment in Cushing's disease Eur. J. Endocrinol., January 1, 2007; 156(1): 91 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Weil, A. O. Vortmeyer, L. K. Nieman, H. L. DeVroom, J. Wanebo, and E. H. Oldfield Surgical Remission of Pituitary Adenomas Confined to the Neurohypophysis in Cushing's Disease J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2656 - 2664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R T Netea-Maier, E J van Lindert, M den Heijer, A van der Eerden, G F F M Pieters, C G J Sweep, J A Grotenhuis, and A R M M Hermus Transsphenoidal pituitary surgery via the endoscopic technique: results in 35 consecutive patients with Cushing's disease. Eur. J. Endocrinol., May 1, 2006; 154(5): 675 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Taguchi, T Takao, Y Iwasaki, M Nishiyama, K Asaba, and K Hashimoto Suppressive effects of dehydroepiandrosterone and the nuclear factor-{kappa}B inhibitor parthenolide on corticotroph tumor cell growth and function in vitro and in vivo J. Endocrinol., February 1, 2006; 188(2): 321 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Esposito, J. R. Dusick, P. Cohan, P. Moftakhar, D. McArthur, C. Wang, R. S. Swerdloff, and D. F. Kelly Early Morning Cortisol Levels as a Predictor of Remission After Transsphenoidal Surgery for Cushing's Disease J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 7 - 13. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
