Use of the histological pseudocapsule in surgery for Cushing disease: rapid postoperative cortisol decline predicting complete tumor resection

Clinical article

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Subnormal postoperative serum cortisol levels indicate successful surgery and predict long-term remission of Cushing disease. Given the short serum half-lives of adrenocorticotropic hormone (ACTH) and cortisol, it is unclear why the decline in cortisol postoperatively is delayed for 18–36 hours. Furthermore, the relevance of the rate of cortisol drop immediately after surgery has not been investigated.


Patient data were analyzed from a prospectively accrued database. After surgery, cortisol replacement was withheld and serum cortisol measurements were obtained every 6 hours until values of 1.0–2.0 μg/dl or less were reached. The authors selected patients in whom serum cortisol dropped to 2 μg/dl or less after surgery (101 patients). Tumor resection was categorized as follows: 1) complete resection using the histological pseudocapsule as a surgical capsule, 2) complete piecemeal resection), 3) known incomplete resection, and 4) total hypophysectomy.


The median time to reach a cortisol level of less than or equal to 2.0 μg/dl was 9.9, 19.4, 25.3, and 29.5 hours with hypophysectomy, pseudocapsule, incomplete resection, and piecemeal techniques, respectively. Pseudocapsule resection produced a faster decline in cortisol than piecemeal techniques (p = 0.0001), but not as rapid a decline as hypophysectomy (p = 0.033).


Complete resection by other techniques is associated with delayed cortisol decline compared with pseudocapsule surgery, which may represent the product of residual tumor cells and therefore may explain the higher rate of recurrent disease associated with piecemeal techniques. The prompt drop in cortisol after hypophysectomy compared with patients with pseudocapsule surgery suggests that the corticotrophs of the normal gland can secrete ACTH for 10–36 hours after surgery despite prolonged and severe hypercortisolism.

Abbreviation used in this paperACTH = adrenocorticotropic hormone.

Article Information

Address correspondence to: Stephen J. Monteith, M.D., Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia 22908. email:

Please include this information when citing this paper: published online January 27, 2012; DOI: 10.3171/2011.12.JNS11886.

© AANS, except where prohibited by US copyright law.



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    Flow diagram demonstrating the distribution of tumors and treatments.

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    Graphs showing the results of Kaplan-Meier analysis. A: Comparison of cortisol nadir in contained tumors resected by the pseudocapsule technique, contained tumors resected by piecemeal techniques, invasive tumors known to be incompletely resected, and hypophysectomy. Note the delay in serum cortisol decline in the groups in which the tumor was invasive, or removed piecemeal, compared with the group in which the tumor was removed using the histological pseudocapsule as a surgical capsule. B: Comparison of cortisol nadir in invasive tumors with incomplete resection and complete resection of contained tumors by piecemeal techniques. Note there is no statistically significant difference between the curves (p = 0.792), suggesting that piecemeal techniques may leave residual tumor cells behind, accounting for the delayed serum cortisol decline compared with pseudocapsule surgery. C: Comparison of cortisol nadir in tumors contained within the pituitary and removed via pseudocapsule resection compared with complete resection of by other piecemeal methods. D: Comparison of cortisol nadir in pseudocapsular resection and total hypophysectomy. The difference between these 2 groups is that there are residual corticotrophs in the normal pituitary gland after selective in which the pseudocapsule technique was used for removal of the tumor, but there is no residual normal gland after total hypophysectomy. Note the fraction of patients with continued cortisol levels exceeding 2 μg/dl for 10–30 hours after surgery, indicating continued transient secretion of ACTH for as long as 36 hours despite the prolonged hypercortisolism of Cushing disease preceding surgery.

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    Serial postoperative serum cortisol and ACTH values in 3 patients whose tumor was removed using the pseudocapsule resection technique. Note that the pattern of cortisol decline closely follows the ACTH curve, indicating that the drop in serum cortisol after surgery is linked to the drop in serum ACTH and suggesting that the slower rate of cortisol decline compared with that of the total hypophysectomy patients is dependent on the function of the corticotrophs within the remaining normal pituitary gland.

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    Photomicrograph demonstrating ACTH immunohistochemistry of an adenoma (right area of the image) and rim of surrounding pituitary (left area of the image) removed from a patient with Cushing disease in whom serum cortisol reached its nadir of less than 1.4 μg/dl and 24-hour urine free cortisol of less than 1.2 μg in the first few days after surgery. The ACTH staining is positive for corticotrophs within the normal gland, indicating storage of ACTH despite exposure to prolonged and severe hypercortisolism. Asterisk indicates the margin of the pituitary gland. Magnification × 100.



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