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Diagnostic Errors after Inferior Petrosal Sinus Sampling

Neuroendocrine Clinical Center (B.S., L.K., K.M., S.G., A.K., B.M.K.B.), Division of Neurosurgery (B.S.), Biostatistics Center (D.J.D.), and Department of Radiology (A.W.), Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Brooke Swearingen, ACC 331, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114. E-mail: bswearingen{at}partners.org.

Although inferior petrosal sinus sampling (IPSS) is useful in the evaluation of Cushing’s syndrome, false negative cases have been described, and many patients presumed to have ectopic tumors based upon negative IPSS remain without a final diagnosis. These patients are often managed as if they have as yet undiscovered ectopic tumors. To test this assumption, we conducted a retrospective review of our results to determine the ultimate diagnoses after IPSS. Between 1986 and 2002, 179 patients underwent 185 IPSS procedures as part of their evaluation for Cushing’s syndrome. Confirmed diagnoses were available for 149 patients (83%): 139 patients had pituitary adenomas (94%), eight had bronchial carcinoids (5%), and two had adrenal tumors (1%). Threshold criteria for a pituitary source were defined as an inferior petrosal sinus to peripheral (IPS:P) basal ratio of 2:1 or greater without CRH or an IPS:P ratio of 3:1 or greater after CRH stimulation. There were nine patients in whom the IPS:P ratio failed to meet threshold criteria after successful sampling, but were nonetheless found to have pituitary tumors after transsphenoidal exploration (false negatives). Eight of these had received CRH and had a significant rise (>35%) in peripheral ACTH levels after CRH treatment, even though the IPS:P ratio did not reach the threshold. There were two patients in whom the IPS:P ratio reached threshold criteria, and ectopic tumors were demonstrated as the source of ACTH overproduction (false positives). The sensitivity after CRH stimulation was 90% (95% confidence interval, 80.8–95.5%) with a specificity of 67% (95% confidence interval, 11.4–94.5%). The positive and negative predictive values were 99 and 20%, respectively. Our data show that patients with an IPS:P ratio suggestive of a nonpituitary source of ACTH overproduction may still have Cushing’s disease. Analyzing the CRH-stimulated peripheral ACTH levels in addition to the standard IPS:P ratios may provide improved diagnostic accuracy. Transsphenoidal exploration should be considered in all cases of unsuccessful sampling and in those cases for which no ectopic source can be identified after further body imaging, even if the IPSS is negative, and especially if peripheral ACTH levels rise significantly with CRH stimulation.

This study was presented in part at the 2003 annual meeting of the Pituitary Society, New York, NY.

Abbreviations: CI, Confidence interval; IPS, inferior petrosal sinus; IPS:P ratio, IPS to peripheral ratio; IPSS, IPS sampling; MRI, magnetic resonance imaging; ROC, receiver operating characteristics; UFC, urinary free cortisol.

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