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Intraoperative Adrenocorticotropin Levels During Transsphenoidal Surgery for Cushing’s Disease Do Not Predict Cure

Division of Endocrinology (K.E.G., D.M.C., M.H.S.), Oregon Health Sciences University, Portland, Oregon 97201; Endocrine Research Laboratory (H.R.), St. Luke’s Medical Center, and Department of Medicine (H.R.), Medical College of Wisconsin, Milwaukee, Wisconsin 53215; Department of Radiology (S.L.B.), Dotter Interventional Institute and Division of Neurosurgery (S.L.B.),Oregon Health Sciences University, Portland, Oregon 97201

Address all correspondence and requests for reprints to: Kathryn E. Graham, M.D., Division of Endocrinology L-607, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201.

	Abstract

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Recently, intraoperative rapid immunochemiluminometric assay (ICMA) ACTH measurements have been used to evaluate the completeness of resection of ectopic ACTH-secreting tumors. This study evaluates whether this method can be applied to patients undergoing transsphenoidal surgery (TSS) for Cushing’s disease to predict complete pituitary tumor resection.

Eighteen patients with Cushing’s disease undergoing TSS had plasma ACTH concentrations measured by a standard ICMA every 10 min for 1 h immediately after pituitary tumor removal. Patients were evaluated postoperatively for cure by standard criteria. ACTH levels were evaluated for percentage decrease from baseline at each time point.

Patients who were cured (n = 11) had statistically greater decreases in ACTH levels (mean decrease 54%) than patients who were not (n = 7; 26% mean decrease, P < 0.04). By Receiver-Operator Characteristic (ROC) analysis, a reduction of at least 40% best predicted which patients were cured and which were not cured. This level of reduction was observed in 82% of cured patients, and a reduction of less than 40% was observed in 71% of those not cured. The analysis misclassified 4 of the 18 patients, resulting in a diagnostic accuracy of 78%.

Although the mean maximal decrease in ACTH concentrations after tumor removal was significantly different between cured and not cured patients with Cushing’s disease, it was less dramatic than results in the previous ectopic ACTH study. This may relate to incomplete suppression and/or surgical manipulation of normal pituitary corticotrophs in patients with pituitary disease. In summary, in contrast to the ectopic ACTH syndrome, decline of plasma ACTH during TSS does not accurately predict complete tumor resection.

	Introduction

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TRANSSPHENOIDAL surgery (TSS) to remove pituitary ACTH-producing microadenomas is a highly effective treatment for Cushing’s disease. Unfortunately, these tumors are usually quite small, milky or semi-solid in consistency, and can be difficult to locate. In cases where a typical tumor is not encountered, the surgeon must decide intraoperatively whether to continue exploration of the pituitary gland or perform a hypophysectomy or hemihypophysectomy. In addition, approximately 5% of ACTH-secreting pituitary tumors are macroadenomas, which can be difficult to resect completely (1).

Recently, intraoperative measurement of the disappearance of ACTH from the plasma by a rapid immunochemiluminometric assay (ICMA) during surgical resection of ectopic ACTH tumors was shown to predict complete tumor resection (2). We designed the current prospective study of pituitary Cushing’s disease to determine if intraoperative ACTH disappearance during TSS would predict complete tumor resection, and therefore, cure of Cushing’s disease. If predictive, application of the rapid ICMA could be of benefit in assessing intraoperatively the need for continued exploration to achieve complete tumor resection in patients with corticotroph adenomas.

	Subjects and Methods

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Experimental Subjects

Eighteen patients (15 women and 3 men) with Cushing’s disease undergoing TSS at Oregon Health Sciences University were prospectively evaluated with intraoperative plasma ACTH measurements. Informed consent for research evaluation was obtained and approved by the Institutional Review Board. ACTH-dependent hypercortisolism was confirmed preoperatively in all patients by history, physical examination, and standard laboratory tests including measurement of 24-h urine free cortisol (UFC) and plasma ACTH levels. The pituitary source of ACTH secretion was confirmed by cavernous sinus sampling utilizing oCRH (3). No patient had evidence of a macroadenoma (>1 cm lesion on magnetic resonance imaging).

Methods

Samples for peripheral plasma ACTH levels were drawn every 10 min, starting from the time of complete pituitary tumor removal as determined by the surgeon (t = 0 min), and continuing for one hour (t = 60 min). ACTH levels were measured by a standard ICMA (Nichols Institute, San Juan Capistrano, CA) with normal range 9–52 pg/mL (2–11 pmol/L), sensitivity 2 pg/mL (0.4 pmol/L), and intra- and interassay coefficients of variance of less than 10%. All samples from a single patient were measured in the same assay within two days of surgery. Glucocorticoids were not administered preoperatively and were withheld during the sampling period. Patients were evaluated for cure of Cushing’s disease (indicating complete tumor resection) by a serum cortisol of less than 2 ug/dL (<55 nmol/L) on the second post-operative day after withholding hydrocortisone for 24 h (4).

ACTH disappearance curves were generated for each patient, and percent of ACTH remaining compared to baseline (t = 0 min) at each time point was plotted. Maximal percent decreases in ACTH levels in cured vs. not cured patients were compared by two-tailed t-test. Data were analyzed for the percent decrease in ACTH that optimally separated cured from not cured patients by ROC curve analysis (5). Diagnostic performance characteristics (sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy) were calculated for this optimal cut-off by standard formulas.

	Results

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All patients underwent TSS without complications. There was no further manipulation of the pituitary gland after the start of the sampling period, there were no significant hemodynamic changes noted during surgery, and the surgical procedure was completed by the end of the sampling period in all patients. Of the 18 patients, 11 were considered cured, while 7 patients had evidence of persistent hypercortisolism. Typical gross tumor was visualized by the surgeon in all patients except one; that patient had indeterminate pathology, but was cured of her hypercortisolism by TSS. However, only 7 of the 11 cured patients and 4 of 7 patients not cured had histologic evidence of an ACTH immunostaining adenoma.

ACTH disappearance curves are shown in Fig. 1 for patients who were cured and in Fig. 2 for patients who were not cured by surgery. Among the patients who were cured, there were small decreases in ACTH levels in all but one of the patients. Three cured patients demonstrated increasing ACTH levels after surgery. There were also small decreases in ACTH levels in some of the patients who were not cured by surgery.

View larger version (21K): [in this window] [in a new window]   Figure 1. ACTH disappearance curves for patients shown to be cured. The percent of ACTH remaining compared with baseline after tumor removal for each patient is plotted during the 60 min sampling period. The upper solid line represents baseline (100% of baseline ACTH level, indicating no change in ACTH level). The lower solid line represents the percent reduction (40%) in ACTH that optimally separates patients who were cured from those who were not, as determined by ROC analysis.

View larger version (18K): [in this window] [in a new window]   Figure 2. ACTH disappearance curves for patients shown to be not cured. The percent of ACTH remaining compared with baseline after tumor removal for each patient is plotted during the 60 min sampling period. Note logarithmic scale. Shown again is the upper solid line representing baseline (100%) and the lower solid line representing percent reduction (40%) in ACTH that optimally separates patients who were cured from those who were not.

View larger version (17K): [in this window] [in a new window]   Figure 3. Maximal decrease in ACTH in cured patients vs. patients not cured. There was a statistically significant greater reduction in ACTH levels in patients who were cured (54% vs. 26%, P < 0.04 by two-tailed t-test).

	Discussion

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The second difference between the two studies was the rapidity of ACTH decline. In the previous study of the ectopic ACTH syndrome, sampling began at the point of vascular ligation, resulting in an abrupt removal of the ACTH source. In contrast, in our patients with pituitary tumors, sampling began at the end of pituitary tumor resection, which can take as long as 15–20 min. Thus, there is no exact time point at which ACTH is suddenly withdrawn, and there may have been partial reductions in ACTH levels before the start of sampling. Measuring a baseline sample before tumor resection might have eliminated this confounder. However, we would still expect a 50% decline in ACTH after 15 min of sampling, based on the half-life of ACTH (7). Because this degree of ACTH reduction was not achieved in all patients over the course of the sampling period, it is likely that normal corticotrophs provided an additional source of ACTH. In the study of patients with the ectopic ACTH syndrome, a rapid decline in ACTH levels made use of the intraoperative rapid ACTH ICMA a helpful adjunct to frozen section analysis. In patients with pituitary tumors, the slower ACTH declines that we observed precluded use of the intraoperative assay to guide surgical therapy.

The final difference between the two studies is the response of patients who were not cured by surgery. Two patients with the ectopic ACTH syndrome who were not cured showed no significant decline in ACTH after purported tumor removal (2, Raff H., unpublished observations). In contrast, we observed decreases greater than 40% in two of the seven patients who were not cured. This may relate to a decrease in tumor load without complete tumor removal or to intrinsic variability in pituitary tumor ACTH secretion (8). Of note, three patients not cured by surgery did not have histologic evidence of pituitary tumors. Because of their size and consistency, these tumors are often not recovered for analysis (9). Given the high accuracy of cavernous sinus sampling for distinguishing pituitary tumors (3), it is still likely that our patients with negative histology actually did have pituitary tumors that were not found at surgery.

This analysis utilized a standard ICMA to measure plasma ACTH levels, so that results were not available until after surgery. If our results had shown accurate prediction of cure with rapid ACTH disappearance, we would have measured ACTH levels in the same samples utilizing the rapid ICMA. However, application of the rapid ICMA would not improve the results, since the rapid incubation has less sensitivity and higher intraassay variability than the standard incubation (10).

In summary, although there were significant differences in the mean decrease in intraoperative plasma ACTH levels between patients who were cured of Cushing’s disease and those who were not, accuracy was only 78%, and patients were misclassified in both groups. This may relate to incomplete suppression of normal pituitary corticotrophs from less severe hypercortisolism or to the avoidance of pre- and perioperative glucocorticoids that might have suppressed ACTH release. In addition, surgical stress and mechanical manipulation of the pituitary may have resulted in ACTH release. Although plasma ACTH disappearance is highly predictive of complete tumor resection and cure in the ectopic ACTH syndrome, it appears to be of limited value in pituitary Cushing’s disease.

Received November 19, 1996.

Revised February 24, 1997.

Accepted March 5, 1997.

	References

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1. Laws ER. 1987 Pituitary surgery. Endocrinol Metab Clin North Am. 16:647–665.[Medline]
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3. Graham KE, Samuels MH, Cook DM, et al. 1996 A direct comparison of cavernous sinus sampling to inferior petrosal sinus sampling in the evaluation of patients with ACTH-dependent Cushing’s syndrome. Proceedings of the Tenth International Congress of Endocrinology, San Francisco, 1996, p. 715.
4. Trainer PJ, Lawrie HS, Verhelst J, et al. 1993 Transphenoidal resection in Cushing’s disease: undetectable serum cortisol as the definition of successful treatment. Clin Endocrinol. 38:73–78.[Medline]
5. Centor RM. 1985 A Visicalc program for estimating the area under a receiver operating characteristic (ROC) curve. Med Decis Making. 5:139–148.
6. Reeves WB, Andreoli TE. 1992 The posterior pituitary and water metabolism. In: Wilson JD, Foster DW, eds. Williams textbook of endocrinology. 8th ed. Philadelphia: WB Saunders; 318–319.
7. Tranmanesh A, Lizarralde G, Veldhuis JD. 1993 Coordinate activation of the corticotropic axis by insulin-induced hypoglycemia: Simultaneous estimates of beta-endorphin, adrenocorticotropin, and cortisol secretion and disappearance in normal men. Acta Endocrinol. 128:521–528.
8. Liu JH, Kazer RR, Rasmussen DD. 1987 Characterization of the twenty-four hour secretion patterns of adrenocorticotropin and cortisol in normal women and patients with Cushing’s disease. J Clin Endocrinol Metab. 64:1027–1035.[Abstract]
9. Wilson CB. 1984 The long-term results following pituitary surgery for Cushing’s disease and Nelson’s syndrome. In: Black PM, Zervas NT, Ridgway EC, Martic JB eds., Secretory tumors of the pituitary gland. 1st ed. New York: Raven Press; 289.
10. Raff H, Shaker JL, Nelson DK, Findling JW. 1994 Rapid measurement of corticotropin (ACTH) with a modified immunochemiluminescent assay. Clin Chem. 40:1344.[Free Full Text]

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