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Departments of Endocrinology and Metabolism (A.M.P., M.O.v.A., N.R.B., J.W.A.S., F.R., J.A.R.) and Neurosurgery (H.v.D., P.J.S.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Address all correspondence and requests for reprints to: Alberto M. Pereira, M.D., Ph.D., Department of Endocrinology and Metabolism, C4-R, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: a.m.pereira{at}lumc.nl.
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Abstract |
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Five patients (9%) had recurrent Cushing’s disease during a median follow-up of 7 yr. Recurrence occurred in four of 24 (17%) patients with a follow-up of more than 10 yr. Therefore, cortisol levels above 138 nmol/liter, obtained 2 wk after TS, should be repeated, because they do not predict persistent Cushing’s disease in 27% of those patients. Postoperative cortisol levels do not positively predict recurrence of disease during long-term follow-up of initially cured patients.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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). However, low postsurgical cortisol levels even when defined according to the most stringent criteria, like postoperative serum cortisol levels less than 50 nmol/liter or adequate suppression on low-dose dexamethasone testing, failed to predict long-term recurrence in 11–15% of patients (9, 11). Conversely, a remarkable phenomenon has been observed in two patients who were cured by TS, but in whom unsuppressed postoperative cortisol levels in subsequent weeks decreased to 200 nmol/liter in one, and even to undetectable levels in the other patient (13). At the Leiden University Medical Center, TS for Cushing’s disease has been performed by a single neurosurgeon (H.v.D.) since 1978. We audited our data retrospectively and report the outcome of TS in 80 consecutive patients with Cushing’s disease, performed between 1978 and 2002. We focused on the predictive value of postoperative cortisol levels for cure as well as recurrence. A subgroup of 24 patients, cured by the initial operation and with postoperative follow-up of more than 10 yr, was analyzed separately. In addition, we investigated the predictive value of other parameters like tumor size.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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)We evaluated 81 consecutive patients who underwent TS for Cushing’s disease between 1978 and 2002, 72 patients as primary treatment and nine secondary to failure of earlier instituted therapy (unilateral adrenalectomy followed by pituitary irradiation). Eight of 81 patients were operated by TS twice and one patient three times, but in our analysis we focused on the first operation, unless stated otherwise. One patient died 3 d after the operation due to cardiorespiratory failure, leaving 80 patients for the first postoperative evaluation. The immediate postoperative follow-up could not be extended because of insufficient data in one patient and because of acute cardiac death after 3 months in another. Postoperative cortisol values in these patients were 70 and less than 50 nmol/liter, respectively. We therefore present the outcome of 78 patients, which could be evaluated with a follow-up of 12 months to 24 yr. Informed consent was obtained from all these patients. The mean age of the patients was 37 yr (range, 12–81 yr), and 80% were female patients. Thirty-two patients with a follow-up duration of more than 10 yr after surgery were analyzed separately. The mean age of these patients was 38 yr (range, 19–68 yr), and 81% were female.
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The diagnosis of Cushing’s disease was made on clinical grounds together with biochemical confirmation of Cushing’s disease, based on the following tests: increased 24-h urinary free cortisol (UFC) excretion (criterion > 220 nmol), failure of serum cortisol to suppress after low-dose dexamethasone (one evening dose of 1 mg or 2 mg/d for 48 h), suppression of serum cortisol during a 7-h iv dexamethasone suppression test as described by Biemond et al. (14), and an exaggerated or normal response of serum cortisol and ACTH on iv CRH stimulation (15). Pituitary imaging by computed tomography or magnetic resonance imaging with iv contrast was performed in all patients. In those patients in whom the radiological findings with respect to the visualization of a pituitary adenoma were inconclusive, bilateral, simultaneous sampling of the inferior petrosal sinuses was performed (23 patients, 28% of cases).
Treatment
Presurgical treatment with cortisol lowering agents, metyrapone or ketoconazole, was given to 40 patients.
At the day of surgery, dexamethasone was started (1 mg/6 h). From the first postoperative day, dexamethasone was gradually decreased from 1 mg/12 h to 0.5 mg/d on the fifth postoperative day. A hydrocortisone substitution dose (30 mg, in recent years 20 mg/d divided in two doses) was given from the sixth postoperative day until the day before endocrinological evaluation. The interval between the last dose of dexamethasone and the first measurement of fasting plasma cortisol was at least 120 h.
Follow-up
The first postoperative assessment of cortisol and ACTH secretion was performed at 0900 h in the second postoperative week, 24 h after the last dose of hydrocortisone. Dynamic stimulation tests were performed with an iv bolus of insulin (0.1 IU/kg body weight) or with 10 IU lysin-vasopressin im, and since 1983 with an iv bolus of CRH (100 µg human CRH). Serum cortisol concentrations (and since 1986 also plasma ACTH) were measured in all tests at baseline and every 15 min thereafter for 90 min.
Patients with basal serum cortisol concentrations less than 138 nmol/liter and insufficient reaction after stimulation with CRH, an insulin tolerance test, or lysin/vasopressin were considered hydrocortisone dependent. These patients were reevaluated after 6 months by measurement of fasting morning serum cortisol concentrations after hydrocortisone withdrawal of 24 h. Patients with serum cortisol concentrations greater than 138 nmol/liter and a peak cortisol of more than 550 nmol/liter after stimulation were considered to be hydrocortisone independent. Patients with basal serum cortisol concentrations greater than 138 nmol/liter were reevaluated with fasting morning cortisol measurements every 2–4 wk within the first 3 months, 6 months after surgery, and annually thereafter. From the 6 months after the operation onward, the biochemical evaluation for all the hydrocortisone-independent patients included an annual evaluation with a low-dose dexamethasone suppression test as well as two 24-h UFC measurements.
Criteria for cure and relapse
Clinical cure was defined 6 months after surgery by dependency on hydrocortisone substitution according to the above-mentioned criteria or by hydrocortisone independency without any biochemical signs of hypercortisolism and regression of the clinical signs.
Biochemical cure was defined as normal suppression to 1 mg oral dexamethasone (cortisol < 100 nmol/liter the following morning) and normal 24-h UFC excretion on two consecutive samples. Persistent Cushing’s disease was defined as failure to fulfill clinical and biochemical criteria for remission after the first operation and before a second intervention.
Relapse was defined as the recurrence of hypercortisolism, reflected in insufficient suppression of plasma cortisol to 1 mg oral dexamethasone (cortisol > 100 nmol/liter the following morning), on more than one occasion and/or abnormal 24-h UFC excretion on two consecutive samples and reoccurrence of clinical signs.
Assays
Cortisol was measured with three different immunoassays over time. Between 1978 and 1986, cortisol was measured by in-house RIA with an interassay coefficient of variation of 10% and with a detection limit of 50 nmol/liter. Between 1986 and 1994, a fluorescence energy-transfer immunoassay Syva-Advance (Syva Company, Palo Alto, CA) was used, with an interassay variation coefficient of 3.6–6.1% and a detection limit of 50 nmol/liter. From 1994, cortisol was measured by fluorescence-polarization assay on a TDx (Abbott Laboratories, Abbott Park, IL). The interassay variation coefficient is 5–6% above 500 nmol/liter and amounts to 12% under 200 nmol/liter. The detection limit is 20 nmol/liter. The methods correlated well with each other, and therefore no correction factors were introduced for follow-up of patients.
ACTH was measured since 1986 (n = 60 patients) using an immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a detection limit of 3 ng/liter. The intra- and interassay average variations ranged from 2.8–7.5% across the sample range observed.
Statistics
Differences between groups were analyzed using the two-tailed Student’s t test for unpaired samples, using SPSS for Windows software version 10.0 (SPSS, Inc., Chicago, IL). Receiver operating characteristic (ROC) curves were constructed to describe the relationship between sensitivity and specificity at various cut-off levels, using all postoperative cortisol values measured 2 and 12 wk after surgery, respectively. The cut-off value between 50 and 200 nmol/liter was increased, in steps of 2 nmol/liter, to determine the optimal combination of sensitivity and specificity. Univariate and multivariate logistic regression analyses were performed to determine possible independent predictors of remission like adenoma size, preoperative cortisol concentration, pretreatment with cortisol lowering agents, and postsurgical ACTH concentration. P < 0.05 was considered significant.
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Results |
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TS cured Cushing’s disease in 56 of the initial 78 patients (72%) at the evaluation at 6 months postoperatively.
Serum cortisol concentrations (Figs. 1
and 2)
Two weeks postoperatively, 37 of 78 (47%) of the patients had fasting plasma cortisol concentrations less than 50 nmol/liter (two macroadenomas), and 11 patients (14%) had plasma cortisol concentrations between 50 and 138 nmol/liter (one macroadenoma). All of these patients appeared later to be cured of Cushing’s disease. In the 2 wk postoperatively, a plasma cortisol level less than 50 nmol/liter identified 66% of the cured patients (37 of 56 patients), and a plasma cortisol concentration less than 138 nmol/liter identified 86% of the cured patients. The remainder of the patients (n = 30, 38%) had plasma cortisol concentrations greater than 138 nmol/liter (nine macroadenomas); of these, eight appeared to be cured of Cushing’s disease during long-term follow-up. Thus, with regard to the effect of adenoma size on postoperative cortisol concentrations, five of eight (63%) cured macroadenomas had postoperative cortisol values at 2 wk above 138 nmol/liter (mean, 301 ± 95 nmol/liter) vs. only two of 48 (4%) of cured microadenomas (mean, 61 ± 9 nmol/liter) (P < 0.05).
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Two weeks postoperatively, ACTH values ranged from less than 3 to 226 ng/liter (mean ± SEM, 29.1 ± 5.4 ng/liter). The ACTH values of the patients who were in remission were significantly lower than those of the failures (16 ± 3 vs. 61 ± 15 ng/liter; P < 0.001).
Serum cortisol concentrations at 3 months
Three months after the operation, six of the 30 patients with initial cortisol concentrations above 138 nmol/liter had cortisol concentrations less than 50 nmol/liter. In these six patients, initial fasting cortisol levels were 407 ± 95 nmol/liter (mean ± SEM), but postabsorptive cortisol levels decreased, reaching a nadir less than 50 nmol/liter, 6–12 wk after surgery. Remarkably, five of these six patients had macroadenomas, whereas one patient had an adenoma of 9 mm (Table 2). The remaining 24 patients (31% of all assessable patients) had persistent cortisol concentrations greater than 138 nmol/liter. Four of these patients had macroadenomas. During prolonged follow-up, two of these 24 patients did not develop any clinical or biochemical sign of Cushing’s disease during a follow-up of 2 and 12 yr, respectively. The other 22 patients had both clinical and biochemical signs of persisting Cushing’s disease. The diagnosis of Cushing’s disease in these 22 patients was established by positive ACTH immunostaining in 17 patients, by positive inferior petrosal sinuses in one patient, and by documented remission of disease after pituitary irradiation in the remaining four patients.
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Sensitivity, specificity, positive predictive values, and negative predictive values for cure of cortisol concentrations of 50 and 138 nmol/liter at 2 wk and 3 months after surgery are given in Table 3. The ROC curves and the area under the ROC curves (AUC) are shown in Fig. 2. The AUC for cut-off values at 2 wk was 0.846 (95% confidence interval, 0.76–0.93) and 0.892 (95% confidence interval, 0.82–0.97) for cut-off values at 3 months. The optimal cut-off value to detect and predict remission was 138 nmol/liter 3 months after surgery, with a sensitivity of 94% and a specificity of 79%. The positive predictive value was 87%, and the negative predictive value was 90%.
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The recurrence rate of disease in all initially cured patients was 9% (5 of 56 patients) during a median period of follow-up of 7 yr. Therefore, the long-term cure rate of Cushing’s disease was 65% (51 of 78) for the whole group studied.
Postoperative plasma cortisol levels did not predict positively long-term recurrence of the disease in initially cured patients. Five of 37 patients (14%) with initial postoperative cortisol values less than 50 nmol/liter, who were cured, relapsed after a median of 7.2 yr (range, 2–20 yr). The clinical details of these five patients are described in Table 4. Eleven of the 12 patients with initial postoperative serum cortisol concentrations between 50 and 138 nmol/liter could be evaluated for more than 2 yr after the operation. None of these 11 patients developed a recurrence of the disease. In addition, all six patients with initial postoperative cortisol concentrations above 138 nmol/liter, but who reached plasma cortisol levels less than 50 nmol/liter 6–12 wk after surgery, remained in remission during prolonged follow-up (1–8 yr). Finally, the two clinically cured patients with persistent plasma cortisol levels above 138 nmol/liter did not develop recurrence of the disease.
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Twenty-four of the initially cured patients had a postoperative follow-up of more than 10 yr (median, 14.5 yr; range, 10–24 yr). Four of these patients developed recurrence of disease (16.7%). Only one patient developed recurrence of disease more than 10 yr after the initial operation (patient 5, Table 4).
Predictors of outcome
Preoperative variables (adenoma size, preoperative cortisol concentration, and pretreatment with cortisol lowering agents) did not significantly influence long-term remission rates in multivariate logistic regression analysis. Postoperative ACTH values did significantly influence long-term remission rates. Univariate logistic regression analysis revealed that ACTH was a significant predictor of remission (P = 0.03), but not of relapse.
Outcome in patients with unsuccessful TS
Of the 22 patients with initial failure of surgery, eight patients (two macroadenomas) had a second operation, and one patient (microadenoma) was operated three times. The median time between the two operations was 3 yr. Six of these 10 operations were classified as failures. Thus, long-term cure rates after repeated surgery were 40% in these patients vs. 65% after first surgery in the total group. Fifteen patients underwent subsequent radiotherapy (one patient after the third operation), of whom 13 (87%) are in long-term remission.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Several publications indicate that immediate postoperative serum cortisol levels less than 50 nmol/liter are associated with long-term clinical cure (4, 16). However, in our series no differences in cure rates were found between patients with cortisol levels less than 50 nmol/liter and levels between 50 and 138 nmol/liter. Moreover, all patients with serum cortisol concentrations between 50 and 138 nmol/liter remained in long-term remission. We found the optimal postoperative cortisol cut-off value for prediction of cure of Cushing’s disease by TS to be 138 nmol/liter, measured 6–12 wk postoperatively.
Six patients were cured despite initial postoperative cortisol levels above 138 nmol/liter and showed a remarkable pattern of postoperative cortisol levels (Table 2 and Fig. 1). After initial fasting plasma cortisol levels above 138 nmol/liter measured 2 wk postoperatively, postabsorptive serum cortisol levels decreased, reaching a nadir 6–12 wk after the operation. Interestingly, five of these six patients had macroadenomas, whereas the sixth patient had a relatively large adenoma diameter of 9 mm. All of these patients are still in remission to date during prolonged follow-up. We could not detect any differences with other cured patients in parameters that could predict this sequence of events like pretreatment with cortisol-lowering agents or reaction to postoperative CRH testing. Nevertheless, recent studies indicate differences in biological behavior between micro- and macroadenomas in Cushing’s disease (17). Although there are no differences in the response of micro- and macroadenomas to CRH, significant differences are present in the ACTH and cortisol responses to hexarelin, a GH secretagogue (18). When investigating the proliferation and apoptotic indices in ACTH-secreting adenomas, a significant difference was found in cell growth fraction, being higher in macroadenomas (19). However, it is unclear to us how these differences between micro- and macroadenomas explain the above- mentioned pattern of postoperative cortisol levels in some of these patients with macroadenomas. Another possibility is that (semi)autonomous adrenal nodules were present, which might explain the initial ability to maintain higher cortisol level. Because no ultrasound or computed tomography or magnetic resonance imaging scan of the adrenals was performed, we cannot exclude this possibility. However, postoperative ACTH values in these six patients (Table 2) were comparable to those of the whole group of patients that were in remission (14 ± 4 ng/liter; range, 4–26; vs. 16 ± 3 ng/liter; range, <3 to 82; P = not significant, respectively), which makes the above-mentioned possibility less likely. Given these data, we suggest that in patients with macroadenomas and nonsuppressed early cortisol concentrations, the measurement of postsurgical plasma ACTH has an additional value in the prediction of cure.
Recurrence of Cushing’s disease developed in 9% of the initially cured patients during long-term follow-up of 2–20 yr. Remarkably, the recurrences occurred exclusively in the patients with the lowest postoperative plasma cortisol values, according to the most stringent criteria proposed by others (4, 16). The rate of recurrence of Cushing’s disease was in accordance with other observations using postoperative cortisol cut-off values of 50 nmol/liter: 14% (5 of 37) in our series vs. 11.5% (7 of 61) (see Ref.8 and Table 1). However, in our study there were no recurrences in initially cured patients who had intermediate or even nonsuppressed cortisol levels in the first 2 wk after the operation. Therefore, cortisol levels obtained during the first few weeks after the operation cannot be used to predict recurrence of Cushing’s disease during prolonged follow-up.
It can be argued that the administration of dexamethasone during the first few days after surgery might have resulted in falsely low levels of plasma cortisol obtained in the second week after operation, although the interval between the last dexamethasone administration and the cortisol measurement was at least 120 h. This could explain the recurrence that occurred only in the five patients with the lowest postoperative cortisol levels. However, plasma cortisol levels were also evaluated at additional time points (2, 6, 12, and 26 wk after surgery, as well as annually thereafter) in all patients. The five patients, who had long-term recurrence of Cushing’s disease had undetectable plasma cortisol levels at all these time points, and three of these patients were still hydrocortisone-dependent 1 yr after surgery. The two other patients, who became hydrocortisone-independent, were free of disease as documented by normal 24-h UFC excretion as well as a normal suppression to low-dose oral dexamethasone. Therefore, it is highly unlikely that the perioperative dexamethasone schedule resulted in false-negative serum cortisol concentrations in the patients who exhibited recurrence of disease after many years.
In theory, the preoperative use of steroid biosynthesis inhibitors could also have influenced the cortisol values obtained in the early postoperative period. However, analysis of the data according to absence or presence of pretreatment with ketoconazole and metyrapone did not reveal statistically significant differences between the two groups. Therefore, we think that it is unlikely that our interpretation with respect to the early postoperative cortisol concentrations is influenced by preoperative treatment with steroid biosynthesis inhibitors.
Interestingly, pituitary exploration in patients with inconclusive preoperative radiological investigation of the pituitary identified an adenoma in 87% of cases. This relatively high rate of identification of pituitary adenomas during pituitary exploration is in accordance with published data of other centers (e.g. Ref.7). Moreover, long-term remission rates in these patients did not differ from those with an identified pituitary adenoma on radiological imaging. Apparently, extensive pituitary exploration in experienced hands does not influence cure rate negatively.
Previously, we documented a cure rate of 61% in patients with acromegaly treated by TS by the same pituitary surgeon (20), compared with the surgical cure rate of 72% of Cushing’s disease in the present series. Moreover, TS cured Cushing’s disease in eight of the 12 macroadenomas. Therefore, the cure rate of macroadenomas causing Cushing’s disease was not different from that of microadenomas, a finding that is consistent with our reported series on acromegalic patients operated by the same neurosurgeon (20). We also compared the long-term recurrence rates of acromegaly in initially cured patients during a follow-up of more than 10 yr. The incidence of recurrent disease in acromegaly during prolonged follow-up was 19% (20), which compares well with the value of 17% in patients with recurrent Cushing’s disease during a follow-up of more than 10 yr. This is surprising, because it is believed that the long-term recurrence rate of Cushing’s disease is lower than for other hormonally active pituitary adenomas (21).
In conclusion, a postoperative plasma cortisol level less than 138 nmol/liter is a strong predictor of cure of Cushing’s disease by TS. However, postoperative plasma cortisol levels above 138 nmol/liter, obtained 2 wk after TS, should be repeated, unless there are other strong indicators of persistence of Cushing’s disease. These unsuppressed postoperative cortisol levels did not predict persistent Cushing’s disease in 27% of those patients, especially in macroadenomas. Furthermore, postsurgical cortisol levels do not predict positively the recurrence of disease during long-term follow-up of initially cured patients, because recurrence of disease occurred in our series only in patients with the lowest postoperative plasma cortisol values. Considering the risk of recurrent disease, all patients with Cushing’s disease cured by surgery require long-term follow-up.
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Footnotes |
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Received April 29, 2003.
Accepted September 2, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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