Transsphenoidal Microsurgery for Cushing’s Disease: Initial Outcome and Long-Term Results

Transsphenoidal Microsurgery for Cushing’s Disease:Initial Outcome and Long-Term Results

GARY D. HAMMER, J. BLAKE TYRRELL, KATHLEEN R. LAMBORN, CAROL B. APPLEBURY,ELIZABETH T. HANNEGAN, SCOTT BELL, RIVA RAHL, AMY LU, AND CHARLES B. WILSON

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 ofNeurological 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; andDepartment of Internal Medicine, Beth Israel Deaconess Medical Center (A.L.), Boston, Massachusetts 02215

Untreated Cushing’s disease and the resultant chronically el-evated glucocorticoid levels lead to severe metabolic distur-bances, including diabetes mellitus, obesity, hypertension,muscle wasting, and osteoporosis. Although transsphenoidalresection has become the standard of care for Cushing’s dis-ease with high initial success rates, little information is avail-able on the long-term morbidity and mortality of patients inremission compared with patients with recurrent or persis-tent Cushing’s disease after such treatment. We therefore con-ducted a retrospective study of 289 patients with Cushing’sdisease who underwent transsphenoidal microsurgery for anACTH-secreting adenoma at a tertiary care center exclusivelyby one surgeon (C.B.W.). Postoperative remission wasachieved in 82% (n � 236) of patients, with best initial remis-sion rates observed in patients with grade I (86%) and II (83%)or stage 0 (88%), A (94%), and B (100%) tumors. Male gender,larger tumor size, and higher stage predicted poorer initialoutcome. Long-term follow-up was obtained on 178 patients,

with a median follow-up time of 11.1 yr (range, 0.6–24.1 yr).Thirteen of 150 (9%) of patients in initial remission developedrecurrent disease, and 12 patients underwent additionaltreatment. At last follow-up, only two of these patients hadactive disease. However, of the 28 patients with initial per-sistent disease who had follow-up greater than 6 months, 10patients continued to have active disease at last follow-up.Although overall survival rates in patients with initial remis-sion did not differ significantly from expected compared withthe general population based on age and sex distribution,patients with initial persistent disease had a significant in-crease in mortality compared with the expected mortality.Thus, successful treatment of Cushing’s disease is associatedwith normal long-term survival. These results suggest thatpatients with persistent Cushing’s disease require early andaggressive intervention to attempt to prevent this excessmortality. (J Clin Endocrinol Metab 89: 6348–6357, 2004)

HARVEY CUSHING FIRST described the clinical syn-drome of excess glucocorticoid production in 1932,

and the incidence of Cushing’s disease in the general pop-ulation is estimated at 0.7–2.4 cases/million/yr (1). SinceCushing’s original report, our understanding of the patho-physiology (2), diagnosis, and treatment of this disorder hasimproved dramatically (3). Most patients with Cushing’ssyndrome have ACTH-secreting pituitary corticotrope mi-croadenomas (Cushing’s disease). Untreated Cushing’s dis-ease results in severe metabolic disturbances secondary tochronically elevated glucocorticoid levels, including obesity,diabetes mellitus, hypertension, muscle wasting, and osteo-porosis (3). Cushing catalogued a mean duration of 4.7 yrfrom clinical diagnosis to death in these patients. Later re-ports of untreated patients with Cushing’s disease confirmedthese findings, with an estimated 5-yr survival rate of 50%(4). The treatment of Cushing’s disease classically involvedbilateral adrenalectomy, adrenolytic therapy, and/or pitu-itary irradiation. However, the selective removal of a corti-cotrope microadenoma by transsphenoidal adenomectomyhas become the standard of care for pituitary microadenomas

(5, 6). A recent report concluded that 5- and 10-yr survivalrates in patients treated successfully with current manage-ment techniques are similar to those in age-matched controlsand are significantly better than those in historic untreatedcontrols (7). However, little is known about the long-term(�10 yr) outcome of these patients and the morbidity andmortality associated with Cushing’s disease treated success-fully by transsphenoidal adenomectomy with resultant nor-malized glucocorticoid levels compared with those in pa-tients with persistent and recurrent disease. We thereforeconducted a retrospective review of the hospital and officerecords of 289 patients with Cushing’s disease who under-went transsphenoidal microsurgery for an ACTH-secretingadenoma at University of California-San Francisco (UCSF).The purpose of this study was to determine the long-termoutcome for patients with transsphenoidal resections per-formed at a single institution (UCSF) on ACTH-producingadenomas over the last 25 yr. This report includes additionalfollow-up data on patients described in initial (1–13 yr) stud-ies (8, 9) who had transsphenoidal surgery for Cushing’sdisease before 1988 and an additional new cohort for a totalof 289 patients. Operations were performed exclusively byone surgeon (C.B.W.). This study includes long-term dy-namic follow-up testing with dexamethasone suppressionand constitutes the largest and most comprehensive fol-

Abbreviation: CSF, Cerebrospinal fluid.JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.

0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(12):6348–6357Printed in U.S.A. Copyright © 2004 by The Endocrine Society

doi: 10.1210/jc.2003-032180

6348

low-up report undertaken at a single site regarding treatmentoutcomes in Cushing’s disease.

Patients and Methods

We conducted a retrospective study of 289 consecutive patients withCushing’s disease who met our inclusion criteria and underwent initialtranssphenoidal microsurgery for an ACTH-secreting adenoma at UCSFexclusively by one surgeon (C.B.W.).

Inclusion and exclusion criteria

The records of all patients undergoing surgery between February1975 and March 1998 were reviewed. During this time period, patientswith ACTH-secreting adenomas accounted for approximately 17% ofthose patients undergoing transsphenoidal surgery at UCSF, includingthose less than 18 yr of age and those with Nelson’s syndrome (C. B.Wilson, unpublished observations). The diagnosis of Cushing’s diseasewas based on the patient’s history, characteristic physical exam findings,laboratory data, magnetic resonance imaging (since 1985), selective ve-nous sampling for ACTH, surgical findings, and histopathology. Im-munohistochemistry using antibodies to ACTH was routinely per-formed on surgical specimens since 1987.

Patients were excluded from the study if they were younger than 18yr of age at the time of the surgery, had undergone previous pituitaryor adrenal surgery, or had Nelson’s syndrome.

Surgical procedure, tumor classification, and postoperativeendocrine evaluation

All operations were performed by one surgeon (C.B.W.) as previouslydescribed (10–12). If the surgeon was unable to localize and selectivelyresect an adenoma, in almost all cases he elected to perform total, hemi-,or partial hypophysectomy or to perform a biopsy. In each case, theprimary aim at surgery was exploration of the entire sellar contents andselective removal of an adenoma when possible. In a few cases, if thetumor margin was indistinct, the surgeon removed 2–3 mm of normaladjacent anterior lobe, and the procedure was termed partial hypoph-ysectomy. If the surgeon encountered tissue that appeared abnormal butwas not typical of an adenoma, then he performed biopsy only. In theera before magnetic resonance imaging and central venous sampling forACTH, if no adenoma could be identified, then, with the patient’s priorinformed consent, total hypophysectomy was performed. In subsequentpatients, if no tumor was identified, then hemihypophysectomy wasperformed in those who had undergone central venous sampling withlateralization to one lobe of the anterior pituitary. If the patient had notconsented to total or hemihypophysectomy, the procedure was termi-nated and was classed as a negative exploration. These decisions re-garding the type of procedures performed were made by the surgeonbased on his intraoperative findings and not on the basis of pathologicalresults. Tumors were classified by neuroradiographic and intraoperativefindings as to the size, degree of sellar destruction (grade), and supra-sellar extension (stage) (11, 13).

In the majority of patients, basal or dexamethasone-suppressedplasma and/or urinary cortisol levels were measured postoperatively,within the first week after surgery, either in the hospital or, more re-cently, as an out-patient after discharge. If data in the immediate post-operative interval were not available, then subsequent laboratory datafrom UCSF or from referring physicians obtained within the first 6months after surgery were used to classify the patient as having remis-sion or persistent disease. If no laboratory data within the first 6 monthswere available for review or if pre- or postoperative data were insuf-ficient to establish either the initial diagnosis or the postoperative re-mission/persistence status (see Definitions below), then patients wereexcluded from the study.

Data collection and patient follow-up

Data were recorded on standard forms for subsequent computerentry, 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 wereapproved by the committee on human research at UCSF. Data regardingthe preoperative diagnosis, surgical procedure and findings, and im-

mediate surgical outcome were obtained by review of hospital anddepartmental medical records and the records of referring and consult-ing physicians. These same sources were also reviewed for informationon long-term follow-up.

We attempted to contact all patients living in the United States toobtain current clinical information by telephone interview. If a currentaddress was not available, we attempted to locate the patient by usingmultiple search techniques, including contacting relatives and referringphysicians. Information was obtained regarding the clinical status of allpatients contacted, including the presence or absence of Cushingoidfeatures and symptoms (moon facies, weakness, amenorrhea, weightgain, headache, hypertension, emotional lability, hirsutism, osteoporo-sis, and visual field disturbances). Current medical therapy and anyintervening therapies, such as any additional operations or radiationtherapy, were recorded. All patients were asked if they had taken hor-mone replacement medications and if they had experienced symptomsof either anterior pituitary dysfunction or recurrent Cushing’s disease atany point after surgery.

At the time of contact, patients were asked if they had a recentlaboratory evaluation regarding Cushing’s disease. If so, these data wereobtained from the patient or his/her physician. In addition, each patientcontacted was asked to undergo an overnight 1-mg dexamethasonesuppression test, with the plasma cortisol level determined at a locallaboratory.

For follow-up regarding survival and mortality, if we were unable tocontact the patients, then we used information from medical records,referring physicians, family members, and friends to determine whetherthe patient had died and the date of death. We also conducted a searchusing national databases to determine whether the patient had died orto define the most recent date the patient was known to be alive.

Definitions

Patients were considered to be in initial postoperative remission ifthey had a basal or dexamethasone-suppressed plasma cortisol level of5 �g/dl or less (�140 nmol/liter) determined within the first week aftersurgery. This level of plasma cortisol after 1 mg dexamethasone waschosen because it was the accepted normative value at the time ofinitiation of this surgical series. Patients for whom no immediate post-operative cortisol levels were available but who, within 6 months aftersurgery, had low or normal plasma or urinary cortisol, resolution of theirclinical features, and no additional therapy were also considered to bein initial remission. Patients who had elevated postoperative cortisollevels and those who underwent additional therapy of Cushing’s diseasewithin 6 months were defined as having persistent disease.

Patients who underwent bilateral adrenalectomy after surgery wereclassified as having persisting or recurrent disease as of the date of thatsurgery. We did not attempt to obtain additional laboratory follow-upfor these patients, because laboratory data after adrenalectomy is notreliable. However, these patients were included in the survival analyses.

Patients were defined as being in long-term remission if 6 monthspost surgery they had follow-up information consistent with continuedclinical remission, if they had a plasma cortisol after a 1-mg dexameth-asone test of 5 �g/dl or less (�140 nmol/liter) or a normal 24-h urinaryfree cortisol level at last follow-up, and if they had not undergoneadditional therapy. Three patients who were initially classified as havingpersistent disease had no additional therapy and had resolution of theirclinical features (follow-up times of 4.2, 9.2, and 11.4 yr). These patientshad dexamethasone-suppressed cortisol values of less than 2 �g/dl (�56nmol/liter), less than 0.2 �g/dl (�5.6 nmol/liter), and less than 0.4�g/dl (�11.2 nmol/liter), respectively, and they were, therefore, classedas being in remission at the latest follow-up. A recurrence was definedas an initial remission followed by recurrent hypercortisolism or addi-tional therapy 6 months or more post surgery. Time to recurrence wasdefined as the earlier of recurrent hypercortisolism or an additionaltherapy.

Major complications were defined as death within 30 d of surgery,significant hemorrhage, serious visual impairment, permanent hypop-ituitarism, cerebrospinal fluid (CSF) leak requiring surgical repair, andmeningitis. Minor complications were defined as CSF leaks not requir-ing surgical repair.

Hammer et al. • Cushing’s Disease: Long-Term Surgical Outcomes J Clin Endocrinol Metab, December 2004, 89(12):6348–6357 6349

Statistical analysis

Logistic regression analyses were performed on the variables tumorsize, tumor stage, tumor grade, sex, and age to identify predictors ofinitial remission or persistence. This was done both for each variableindividually and also using a backward multivariate stepwiseprocedure.

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 withthose observed in this study. The expected mortality rates for patients in thisstudy were determined based on person-years of follow-up for each sex andage group. The difference between observed and expected rates was testedusing the exact probabilities of the Poisson distribution (15).

Kaplan-Meier analysis (16) was used to estimate the probability offreedom from recurrence for patients in initial remission and to estimatesurvival curves for both the patients in remission and those with per-sistent disease based on the initial postoperative outcome. Expectedsurvival curves were generated based on standard life-table methodsusing the expected mortality rates (14).

Statistical significance is defined as P � 0.05 using a two-tailed test.

ResultsDemographics and short-term outcomes

Patient population. Our study cohort included 289 patientswho underwent transsphenoidal surgery from February1975 to March 1998. We excluded 53 patients who were lessthan age 18 yr, 38 patients with Nelson’s syndrome, and fourwho had undergone prior transsphenoidal surgery. Threepatients who had negative exploration were excluded be-cause insufficient data were available to establish the diag-nosis. In one patient no records were available; in the othertwo, preoperative endocrine data were equivocal, and post-operative follow-up suggested that they had pseudo-Cush-ing’s (depression in one and alcoholism in the other). Anadditional 13 patients were excluded because we could notobtain data to establish whether they were in postoperative

remission or had persisting disease. These patients had pre-operative laboratory data consistent with Cushing’s disease,and 11 of 13 had positive pituitary pathology confirming thediagnosis.

The median age of our 289 patients at the time of surgerywas 37 yr (range, 18–72 yr). There were 239 (83%) female and50 (17%) male patients. Radiation therapy had been admin-istered to eight patients before surgery.

Tumor classification. The median tumor size in 233 patients forwhom we had data were 6 mm (mean, 7.5 mm; range, 1–30mm). Grade and stage were described for 200 patients, andthe majority of patients had tumors that were confined to thesella turcica without bony erosion of the sella floor (grade Ior II; 96%). In addition, the majority of these adenomas didnot have suprasellar extension or invasion of the cavernoussinus (stage 0; 68%). However, there were eight cases oflocalized perforation of the sellar floor (grade III; 4%) and 34(17%) cases of cavernous sinus extension (stage E; 17%). Notumors exhibited destruction of the sellar floor (grade IV) ormetastatic spread (grade V; Table 1).

Initial surgical procedures and outcomes (Table 2). The majorityof patients (227 of 289, 79%) underwent selective removal ofthe pituitary adenoma (Table 2). In 21% (62 of 289) of patients,no focal tumor was identified by the surgeon, and thesepatients underwent hemi- (or partial) hypophysectomy (25of 289, 8.7%) or total hypophysectomy (23 of 289, 8.0%; seePatients and Methods). A small number of patients underwentnegative pituitary exploration only (four of 289, 1.4%) orbiopsy only (10 of 289, 3.5%).

Overall, of the 289 patients with Cushing’s disease whounderwent transsphenoidal resection of pituitary adenomas

TABLE 1. Tumor classification

n Mean Median Range

Tumor size (mm) 233 7.5 6 1–30

n Initial remission [no. (%)] Persistent disease [no. (%)]

Tumor grade: relationship of adenoma to sella and sphenoid sinusesGrade I 140 121 (86) 19 (14)Grade II 52 43 (83) 9 (17)Grade III 8 5 (63) 3 (38)Grade IV 0 0 0Grade V 0 0 0

Total 200 169 31Missing 89

Tumor stage: extrasellar extensionStage 0 136 119 (88) 17 (12)Stage A 17 16 (94) 1 (6)Stage B 7 7 (100) 0Stage C 6 5 (83) 1 (17)Stage D 0 0 0Stage E 34 22 (65) 12 (35)

Total 200 169 31Missing 89

Grade: Relationship of adenoma to sella and sphenoid sinuses. Intrasellar: I, sella normal or focally expanded, tumor less than 10 mm; II,sella enlarged, tumor larger than 10 mm; sphenoid: III, localized perforation of sellar floor; IV, diffuse destruction of sellar floor, distant spread;V, spread via CSF or blood. Stage, extrasellar extension: suprasellar extension: 0, none; A, occupies cistern; B, recesses of third ventricleobliterated; C, third ventricle grossly displaced; parasellar extension: D, intracranial (intradural); E, into or beneath carvernous sinus(extradural).

6350 J Clin Endocrinol Metab, December 2004, 89(12):6348–6357 Hammer et al. • Cushing’s Disease: Long-Term Surgical Outcomes

during the study period, 236 (82%) patients were found to bein remission postoperatively, whereas 53 patients (18%) hadpersistent disease (Table 2). Remission was achieved in 83%(189 of 227) of those who underwent selective adenoma re-section and in 85% (41 of 48) of those who underwent partialor total hypophysectomy. Only 43% (six of 14) of patientswith exploration only or biopsy only achieved remission.

A total of 253 of 289 (87.5%) patients had pathological con-firmation of Cushing’s disease (pituitary ACTH hypersecre-tion). Of these, 249 patients were diagnosed as having pituitaryadenoma based on histology and/or positive immunostainingfor ACTH. Four patients had a pathological diagnosis of cor-ticotrope hyperplasia. Remission was achieved in 211 of 253(83.3%) of these patients with pathological confirmation of thediagnosis, and 42 of 253 (16.6%) had persisting disease. Thirty-six patients (36 of 289; 12.5%) had negative pathology, and aftersurgery 25 of 36 (69.4%) of these patients were in remission, and11 of 36 (30.6%) had persisting disease.

Surgical remission was analyzed with reference to tumorclassification (Table 1). In patients with grade I and II, ad-enomas (i.e. micro- and macroadenomas confined to the sellaturcica) remission was achieved in 86% and 83%, respec-tively. However, if the tumor had perforated the floor of thesella turcica (grade III), only 63% of patients had initial re-mission. Patients with no suprasellar tumor extension (stage0) or moderate suprasellar extension (stage A or B) had goodsurgical outcomes, with initial remission achieved in 88%,94%, and 100%, respectively. However, if at surgery therewas tumor extension into the cavernous sinus (stage E),initial remission occurred in only 65%. Thus, patients withadenomas confined to the sella turcica or with moderatesuprasellar extension had the best surgical results.

Thirty-one of the patients with persistent disease had sub-sequent therapy within the first 6 months postoperatively.Nineteen patients underwent radiation therapy alone (includ-ing one who underwent �-knife radiosurgery), five underwentbilateral adrenalectomy, and six underwent repeat transsphe-noidal resection. One additional patient underwent repeattranssphenoidal resection and adrenalectomy. The subsequentoutcome of these patients is discussed below.

Predictors of initial outcome. We examined whether gender,tumor size, grade, stage, or patient age would be predictiveof the initial patient outcome using logistic regression. Basedon logistic regression, male gender (P � 0.002), larger tumorsize (P � 0.046), and higher stage (P � 0.003) predictedpoorer outcomes. Using a multivariate logistic model with

backward selection and a criterion of P � 0.05, male genderand higher stage remained in the model (P � 0.03 and P � 0.002,respectively). Because the analysis that included tumor size waslimited by the number for whom tumor size was available, afinal analysis was run including only gender and stage with anincreased number of patients. This analysis found that highertumor stage was statistically significant (P � 0.003), and genderwas marginally significant (P � 0.09; data not shown).

Initial surgical morbidity and mortality. There were three deathswithin 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 infarctionand/or cardiac failure. One other 42-yr-old female patientdied of cardiac arrest 2.5 months after surgery. An additional14 patients had 19 postoperative surgical complications; ofthese, nine were major complications, including three casesof CSF leak requiring surgical repair and two cases each ofmeningitis, hematoma or hemorrhage, and permanent visualloss. There were nine cases of permanent diabetes insipidusand 25 patients with hypopituitarism (including the 23 pa-tients who underwent total hypophysectomy; Table 3).

Long-term outcomes

Patient follow-up. Of the original 289 patients, follow-up forassessment of remission status after 6 months was obtainedfor 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, and99 were followed for 10 yr or more (Table 4). Compared withpatients in whom no long-term follow-up was available,patients who were followed beyond 6 months showed nosignificant difference in the clinical characteristics of gender,age, tumor size, grade, or stage (Table 5). Thus, there is noindication that patients with follow-up are a biased sample.

Patients in initial remission. As outlined in Fig. 1, of the 236patients who were initially in remission, we had informationmore than 6 months post surgery for 150, and we were ableto contact 139. Of the 150 patients, 137 were still in remissionat the latest follow-up. These patients were considered to bein long-term remission only if they had continued clinicalremission, normal values for dexamethasone suppression or

TABLE 2. Initial surgical procedures and outcome

n Initialremissiona

Persistentdiseasea

Surgical proceduresSelective removal 227 189 (83) 38 (17)Total hypophysectomy 23 18 (78) 5 (22)Hemi hypophysectomy 22 20 (91) 2 (9)Partial hypophysectomy 3 3 (100) 0 (0)Negative exploration 4 2 (50) 2 (50)Biopsy only 10 4 (40) 6 (60)

Total 289 236 (82) 53 (18)a Number (percentage).

TABLE 3. Mortality and postoperative complications

n

DeathsWithin 30 d 3

ComplicationsCSF leak (drain) 9CSF surgery 3Meningitis 2Hematoma/hemorrhage 2Transient vision loss 1Permanent vision loss 2Total postoperative complications 19Total patients 14

Hormonal replacementPermanent diabetes insipidus hypopituitarism 9TSH 9FSH/LH 25ACTH 19Total postoperative hormonal replacement 27


24-h urinary free cortisol, and had undergone no additionaltherapy (see Definitions). The median follow-up for those stillin remission was 11.3 yr (range, 0.6–24 yr), and 75% of thepatients had been followed for more than 6 yr. An additional13 patients (13 of 150, 9%) had recurrent disease after 6months. The median time to recurrence for these patients was4.9 yr (range, 1.1–11.1 yr). Kaplan-Meier estimates for theprobability 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 Cush-ing’s disease underwent the following additional proce-dures: seven patients underwent an additional transsphe-noidal resection, three patients underwent radiation therapy,and one patient underwent adrenalectomy. One patient un-derwent transsphenoidal resection and adrenalectomy. Onepatient with recurrent disease had not undergone additionaltherapy at the last follow-up. At their last follow-up, 11 patientswere in remission, and two patients still had active disease.

Patients with persistent disease. Also followed were patients withinitial failure after their primary surgery (Fig. 2). Of the 53patients who displayed initial failure, we had long-term fol-low-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 undergoneadditional 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 includedadditional transsphenoidal surgery in three patients, transsphe-noidal surgery and radiation in two patients, and transsphe-noidal surgery plus adrenalectomy in one patient. Two patientsunderwent radiation therapy alone, and an additional two un-derwent adrenalectomy alone. At last follow-up, five of thesepatients were in remission, and five continued to have persis-tent disease. Ultimately, 18 of 28 patients were in remission atlast follow-up, and 10 had persistent disease.

Dexamethasone suppression testing. The 1-mg overnight dexa-methasone suppression test was performed on 119 of 150 pa-tients with initial remission for whom we had more than 6months of follow-up post surgery. Data for 113 patients fromthis group who continued in clinical remission at the time theywere tested are shown in Table 6A. The mean time from initialtranssphenoidal resection to dexamethasone suppression test-

FIG. 1. Schematic outline of follow-up dataand outcome of patients with initial remission.ADX, Adrenalectomy; TSR, transsphenoidalresection; XRT, x-ray therapy; pts, patients;m, months.

TABLE 4. Follow-up for assessment of remission status

0.5Y FU 2Y FU 5Y FU 10Y FU 15Y FU 20Y FU

Initialremission

150 142 125 83 47 12

Persistentdisease

28 23 20 16 7 0

Totals 178 165 145 99 54 12

Y FU, Years of follow-up.

TABLE 5. Comparison of clinical characteristics of patients withand without long-term follow-up

�6 monthsfollow-up

�6 monthsfollow-upa

P valuefor difference

Gender (M/F) 21/90 29/149 0.57Age (median/range) 37 (18–72) 36 (18–71) 0.80Tumor size (median/range) 6 (2–30) 6 (1–30) 0.15Tumor grade [no. (%)] 0.25

1 46 (65) 94 (73)2 22 (31) 30 (23)3 3 (4) 5 (4)

Tumor stage [no. (%)] 0.92O 49 (69) 87 (67)A 3 (4) 14 (11)B 5 (7) 2 (2)C 2 (3) 4 (3)D 0 0E 12 (17) 22 (17)a Based on follow-up for disease status. Additional patients had

information available on survival status beyond 6 months.


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ing was 12.36 yr. Of these 113 patients, 110 (97%) had post-dexamethasone cortisol values of 5 �g/dl or less (�140 nmol/liter), and 97 patients (86%) had cortisol values of 2 �g/dl or less(�56 nmol/liter). None of the 13 patients with cortisol valuesbetween 3–5 �g/dl (84–140 nmol/liter) had clinical evidence ofrecurrence, and they were presumed to be in remission. Thethree patients with postdexamethasone morning cortisol valuesgreater than 5 �g/dl (�140 nmol/liter) underwent additionalevaluation with 24-h urinary cortisol measurement, and theseresults were normal in each case, confirming remission. Six ofthe 13 patients who had had recurrent disease were also tested(Table 6B). Five of these patients had postdexamethasone cor-tisol values of 5 �g/dl or less (�140 nmol/liter) after additionaltherapy and were also in clinical remission at latest follow-up.The patient with the cortisol value of 26 �g/dl (728 nmol/liter)also had clinical symptoms and features of recurrent hyper-cortisolism (Table 6B). The overnight 1-mg dexamethasone sup-pression test was also performed in 17 of the 28 patients withfollow-up of persistent disease (Table 6C). Of these, 14 hadpostdexamethasone cortisol values of 5 �g/dl or less (�140nmol/liter) and were also in clinical remission at last follow-up.Three patients continued to have persistent disease, with post-dexamethasone cortisol values of 10–11 �g/dl (280–308 nmol/liter; Table 6C).

Mortality. Of the 285 patients who were alive at 6 months postsurgery, we had additional follow-up information regardingsurvival or mortality in 248 (87%), and in 37 (13%) patients wewere unable to obtain any information after 6 months as to theirsurvival or death. The duration of follow-up regarding survivalfor those patients still alive is presented in Table 7. There werea total of 29 deaths in the entire series. As stated above, fourpatients died within 6 months of their initial procedure (three

within 30 d and one at 2.5 months). An additional 25 patientsdied after 6 months (one patient of these 29 was excluded fromthe survival analyses because the exact date of death could notbe determined). Of the 29 patients who died, 23 were female,and six were male.

Of the patients who died after the initial 6-month fol-low-up period, 17 patients were from the group with initialremission, with a median age of death of 71.7 yr (range,35.1–87.9 yr) and a median survival after surgery of 12.7 yr(range, 3.0–21.3 yr). Seven patients with initially persistentdisease also died after 6 months, with a median age at deathof 61.1 yr (range, 49.8–77.2 yr) and a median survival aftersurgery of 13.7 yr (range, 3.6–17.1 yr).

Initial assessment of the survival difference betweengroups (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 ineach group compared with the number of deaths expectedbased on age- and sex-matched population survival statis-tics. Of the 236 patients who were in initial remission aftersurgery, 17 had died, and this cumulative observed mortalityrate did not differ significantly from the expected rate (P �0.28; Fig. 3A and Table 9). Of the 53 patients with initialpersistent disease after surgery, seven patients ultimatelydied. In contrast to the patients with initial remission, thegroup with initial persistent disease had a statistically sig-nificant increase in mortality in males (P � 0.05) and com-bined males and females (P � 0.01) compared with expectedmortality (Fig. 3B and Table 9).

Discussion

The associated clinical sequelae of Cushing’s disease in-cluding obesity, hypertension, and diabetes mellitus are se-rious and potentially fatal. Although transsphenoidal resec-tion of pituitary adenomas has become the treatment ofchoice for Cushing’s disease (5, 6, 9), failure rates have beenshown to range from 10–40% (17, 18), with recurrence ratesup to 25% in patients thought to have been cured in post-operative evaluations of cortisol levels (19). In addition, over

TABLE 6. Dexamethasone suppression results

Cortisol [�g/dl (nmol/liter)] Frequency [no. (%)]

A. Patients in clinical remission at last follow-up1 (28) 79 (69.9)2 (56) 18 (15.9)3 (84) 7 (6.2)4 (112) 2 (1.8)5 (140) 4 (3.5)7 (196)a 1 (0.9)8 (224)a 1 (0.9)

13 (364)a 1 (0.9)

Total 113 (100)B. Patients with recurrence before last follow-up

1 (28) 3 (50.0)5 (140) 2 (33.3)

26 (728) 1 (16.7)

Total 6 (100)C. Patients with initial persistent disease

1 (28) 8 (47.1)2 (56) 4 (23.5)3 (84) 1 (5.88)5 (140) 1 (5.88)

10 (280) 2 (11.76)11 (308) 1 (5.88)

Total 17 (100)a These three patients subsequently had normal 24-h urinary free

cortisol that confirmed remission.

TABLE 7. Duration of follow-up for assessment of survival status

0.5Y FU 2Y FU 5Y FU 10Y FU 15Y FU 20Y FU

Initial remission 184 179 155 98 53 15Persistent disease 40 34 31 21 9 0

Total 224 213 186 119 62 15

These data exclude patients known to have died. Y FU, Years offollow-up.

TABLE 8. Percent survival stratified by initial outcome

YrInitial remission Initial persistent disease

% Survival CI % Survival CI

5 99 98–100 95 88–10010 96 93–100 95 88–10015 85 78–93 84 69–100

Although the graphs for comparison with normal controls begin at6 months post surgery, data for this table are calculated from the timeof surgery. The P value from a log-rank test for the difference insurvival is 0.06.


a decade ago it was suggested that recurrence rates wouldincrease as follow-up periods lengthened (20). The purposeof this study was to ascertain short- and long-term follow-upstatus of patients and to correlate the risk of disease recur-rence/persistence with pre- and postoperative assessments.All patients were operated on by a single surgeon over 25 yr,eliminating the inherent variability in series with multiplesurgeons. For assessment of survival, we conducted retro-spective chart reviews, contacted referring physicians, andsearched national databases. For follow-up assessment of thepatients’ disease activity (remission status), these effortswere supplemented with patient interviews and laboratorytesting (overnight dexamethasone suppression or 24-h uri-nary free cortisol) to provide biochemical assessment of long-term outcome for as long as 23 yr.

Our study confirms that transsphenoidal resection is a safeprocedure for patients with Cushing’s disease, with a lowoverall mortality rate similar to previous reports by us (9)and others (21, 22). The major complication rate of 3.1% in ourstudy is nearly the same as in other reports in the literature.In prior studies, surgical, histopathological, and/or radio-graphic identification of tumors have all proven to predictgood outcome compared with negative diagnostic iden-tification (19, 21, 23, 24). This is logical in that if a tumorcan 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 wereassociated with worse outcomes. In this series, highertumor stage was the strongest predictor of poor surgicaloutcome (P � 0.01). These patients had stage E tumors,

FIG. 3. Kaplan-Meier analysis of observed mortalityrates (dashed lines) among patients in initial remission(A) or with initial persistent disease (B). Solid lines in-dicate expected mortality rates based on age and genderpopulation survival statistics. The y-axis indicates theproportion of patients surviving. The number of yearselapsed since surgery is indicated on the x-axis. Each steprepresents one patient death.


with invasion of the cavernous sinus precluding completesurgical resection.

The definition of a biochemical cure of Cushing’s diseasehas been the subject of much controversy (18, 23, 25), and asubset of patients can recur or relapse after presumed priorcure. As such, a successful outcome after treatment is per-haps better described as a remission. Predicting which pa-tients are at risk for recurrence/relapse is therefore quiteimportant. The immediate postoperative assessment of ad-renal function is proving to be highly predictive of long-termoutcome. Although low to undetectable cortisol levels post-operatively have been reported to predict a recurrence rateof 4.3%, normal or frankly high levels of cortisol postoper-atively result in a 26.3% rate of recurrence (24, 26). In ourexperience, 82% of patients (236 of 289) had low cortisollevels within the first 6 months postoperatively, had noknown additional procedures during that interval, and wereconsidered in initial remission. This is similar to other studiesthat defined initial success rates as a suppressed cortisolmeasurement (20, 21, 24). Furthermore, the initial outcomedata are consistent with our prior studies (9) and similar orbetter than other smaller series showing early remission ratesbetween 70–90% (22, 27, 28). Eighteen percent of patients (53of 289) in this study were not cured postoperatively, as man-ifested in a nonsuppressed cortisol level or an additionalprocedure within the first 6 months of surgery. Many of thesepatients underwent early reoperation or radiotherapy, sim-ilar to the experience of Trainer et al. (29).

Of the 150 patients in initial remission at 6 months for whomwe had more than 6 month follow-up regarding remissionstatus, 13 (9%) recurred some time during the course of follow-up. With so few recurrences, no risk factors could be associatedwith recurrence in these patients. These data do not agree withthe 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-uptimes of over 15 yr, and the risk of recurrence does not appearto be substantially higher after 10 yr, with a 15 yr estimated riskof 11%. Importantly, in patients with initial remission, evenwith recurrent disease, ultimate long-term remission is likely,with a final prevalence of active disease at final follow-up of1.3% (two of 150 patients with initial remission with long-termfollow-up data available for review). However, patients withinitial persistent disease had less successful outcomes, as evi-

denced by both a higher prevalence of persistent disease at finalfollow-up (36%; 10 of 28 patients with initial persistent diseasewith long-term follow-up data) and an increased overallmortality.

The 1-mg overnight dexamethasone suppression test is asimple screening test for Cushing’s syndrome (31). The appro-priate level of suppression is debated; however, patients withCushing’s syndrome usually fail to suppress to 3.6–7.2 �g/dl(100–200 nmol/liter) (32, 33). A cut-off value of 3.6 �g/dl (100nmol/liter) is highly sensitive, with a false negative rate as lowas 2% (34). Suppression to less than 1.8 �g/dl (50 nmol/liter)is highly specific and virtually excludes Cushing’s syndrome(35), as discussed in a recent Cushing’s disease consensus state-ment (36). Using 5 �g/dl or less (140 nmol/liter) as our cut-offfor normal, we used the test as a screening tool to assess thepresence of persistent/recurrent Cushing’s disease with the testperformed in local clinical laboratories. However, the resultshighlight the risk of false positive tests inherent with such ascreening tool. If persistence or recurrence is suspected on thebasis of the 1-mg dexamethasone suppression test, confirma-tory testing should be performed with 24-h urinary free cortisolor late night salivary cortisol measurements.

There was no indication that survival in our patients withinitial remission was different from that of the normal popu-lation (adjusted for age and sex). Our survival data at 5 yr (99%)and 10 yr (96%) for patients in initial remission were compa-rable to the 5 yr (99%) and 10 yr (93%) data reported for patientsin initial remission by Swearingen et al. (7). Our report extendsthese studies and indicates prolonged preservation of survivalat 15 yr in patients with initial remission of disease. In addition,our study indicates that patients with initial persistent diseasehave excess mortality compared with those in initial remissionand to the population at large. The assessment of survival forthis study was limited by the fact that we were not able toascertain current survival status for all patients and had infor-mation on post-6-month survival for only 87% of our patientswho lived more than 6 months postsurgery. However, becausewe used national databases, that allowed searches based onsocial security number and provided information on death, itis likely that our estimates of survival, if biased, would be biasedtoward shorter survival, because if a patient died, we wouldhave been likely to find this out, whereas we considered thefollow-up for the surviving patients to have ended at the datethey were last known to be alive, which could be a substantialunderestimate of the time they had survived after surgery. Thisstrengthens the argument that survival for those in initial re-mission is not less than would be predicted in a normal pop-ulation. It does imply that we may be overestimating the effectof persistent disease in increasing mortality. However, if weassume that all patients not known to be dead were alive at leastto January 2000, the pattern of results remains unchanged (al-beit without as strong a statistical statement; P � 0.05), and theconclusions remain consistent.

Only two modern series have addressed the issue of mor-tality 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 theirpatients received multiple therapies (i.e. only 28 of 41 under-went transsphenoidal surgery as the initial procedure, 18 of 41underwent bilateral adrenalectomy, and 16 of 41 underwent

TABLE 9. Mortality rates for disease status compared to age-and sex-matched normal population

Disease status Observed Expected P value

RemissionMale 2 2.9 0.79Female 15 11.5 0.18Combined 17 14.4 0.28

PersistentMale 4 1.4 0.05Female 3 1.1 0.10Combined 7 2.5 0.01

P values are based on the Poisson distribution and represent theprobability of observing the number of deaths observed or more giventhe number of deaths expected.


radiotherapy). In addition, it appears that eight of 49 (16%) oftheir patients did not undergo treatment. In contrast, Swear-ingen et al. (7) in 1999 reported normal survival in 161 patientsinitially treated by transsphenoidal surgery, followed by earlyrepeat transsphenoidal surgery, adrenalectomy, and/or radio-therapy in those patients with persisting disease or recurrence.The researchers (7) did not find increased mortality in theirpatients with persisting disease; however, none of their patientshad persisting cortisol excess at the time of last follow-up.However, in our series, 10 of 28 (36%) patients classified initiallyas having persisting disease and followed for more than 6months had persisting hypercortisolism at the most recent fol-low-up. These differences suggest that early intervention tocorrect cortisol excess may reverse the excess mortality that weobserved in our patients with persisting disease.

In conclusion, our results with a large series of patients con-firm that initial remission can be achieved in approximately80% of patients with Cushing’s disease. In those patients withinitial remission, our recurrence rate was low, and survivalappears to normalize in those patients who achieved initialremission. However, patients who had initial persistent diseasehad excess mortality. Our results, therefore, suggest that al-though patients in initial remission after transsphenoidal mi-crosurgery appear to have normal survival, patients with per-sisting disease require early and aggressive therapeuticintervention to attempt to prevent excess mortality.

Acknowledgments

We acknowledge our referring and local colleagues, students, resi-dents, and fellows who were involved in all aspects of the challengingcare of these patients over the last three decades.

Received December 23, 2003. Accepted September 12, 2004.Address all correspondence and requests for reprints to: Dr. Gary D.

Hammer, Department of Internal Medicine, Division of Endocrinologyand Metabolism, University of Michigan, 5560 MSRB-II, Box 0678, 1150West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail:[email protected].

This work was supported by donations from grateful patients treatedfor Cushing’s disease by C.B.W. The funding source (unsolicited dona-tions from grateful patients treated by C.B.W.) had no involvement inthe design of the study; the collection, analysis, and interpretation of thedata; or the decision to approve publication of the finished manuscript.

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Transsphenoidal Microsurgery for Cushing’s Disease: Initial Outcome and Long-Term Results

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