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Improved Diagnostic Accuracy of Inferior Petrosal Sinus Sampling over Imaging for Localizing Pituitary Pathology in Patients with Cushing’s Disease

Departments of Medicine (G.L.B., D.A.R., S.E.), Radiology (H.G.), Pathology (K.K.), and Neurosurgery (H.S.S.), University of Toronto, Toronto, Ontario, Canada M5G-1X5

Address all correspondence and requests for reprints to: Dr. Shereen Ezzat, University of Toronto, 600 University Avenue #429, Toronto, Ontario, M5G-1X5, Canada.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
The majority of patients with Cushing’s disease can be cured by transsphenoidal microsurgery; however, precise localization of the pituitary source of ACTH is not always possible by standard imaging techniques. Bilateral venous sampling from the inferior petrosal sinuses (IPSS) is also useful for diagnosing Cushing’s disease, but the interpretation of discordant findings between IPSS and imaging remains problematic. We tested the ability of imaging and IPSS to localize an ACTH-secreting pituitary lesion in comparison to definitive histopathological examination of the pituitary in patients with Cushing’s disease (n = 37). Bilateral IPS catheterization was technically feasible in 32 patients and provided evidence of lateralization in 31 patients. Histological examination confirmed a corticotropic adenoma in 28 patients and corticotropic hyperplasia in 2 patients; Crooke’s hyaline change was found in 7 patients, among whom 1 subsequently was found to have an ectopic sphenoid corticotropic adenoma, and the remainder had suspected microadenomas that were not identified microscopically. Accurate localization of the pituitary lesion was more frequent when based on IPSS results than on imaging studies (70% vs. 49%, P < 0.06). The 2 tests provided directly discrepant results for 8 patients; among these, IPSS was more likely than imaging to agree with final pathology (63% vs. 13%, P < 0.10). Imaging was entirely normal for another 9 patients, in whom IPSS accurately localized the lesion for the majority (89%; 95% confidence interval: 50–99%). We suggest that IPSS is an effective tool for localizing pituitary pathology and planning surgery for patients with Cushing’s disease.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CUSHING’S disease, an ACTH-secreting pituitary tumor, accounts for about two thirds of cases of Cushing’s syndrome (1, 2, 3). As Cushing’s disease can be cured by pituitary microsurgery, accurate localization of the tumor within the gland is essential for selectively removing the lesion and preserving normal pituitary function.

Imaging studies are an imperfect method for identifying corticotropic microadenomas. Scanning by computerized tomography (CT) has a sensitivity of 15–60% (4, 5). Contrast enhanced magnetic resonance imaging (MRI) has been reported to have a sensitivity ranging from 54–91% (4, 6, 7, 8). However, false positives may occur with imaging studies; for example, MRI scanning detects pituitary microadenomas in 10% of the healthy population (9). A safe, accurate, and affordable method for localizing pituitary adenomas would be valuable for managing patients with Cushing’s disease.

Drainage of venous blood from each half of the pituitary gland tends to flow from the ipsilateral cavernous sinus into the inferior petrosal sinus (IPS) and then into the internal jugular vein (10, 11). Because of the proximity of the IPS to the pituitary gland, ACTH levels in the sinus are higher than in the peripheral blood. Inferior petrosal sinus sampling (IPSS), therefore, can be used to assist in the diagnosis of Cushing’s disease. Moreover, IPSS provides an alternative to imaging for localizing the ACTH source within the pituitary gland. However, previous studies have yielded conflicting results on the accuracy of IPSS to localize corticotropic adenomas (12, 13, 14, 15, 16, 17). The focus of this study is to compare the accuracy of IPSS with imaging to localize an ACTH-secreting source definitively established by pituitary histopathology.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Thirty-nine consecutive patients who underwent standard imaging, IPSS, and subsequent transsphenoidal surgery for treatment of Cushing’s disease were identified. Patients underwent IPSS if imaging of the sella or biochemical testing yielded equivocal or conflicting results. One patient was excluded because IPSS was only performed on one side and, therefore, an intersinus gradient could not be calculated. One other patient was excluded because the true location of the ACTH source was never identified despite extensive pathological examination. Hence, 37 patients who underwent bilateral catheterization and for whom a gold standard was available were included in the final sample.

Screening evaluations were conducted on all patients as either a 24-h urinary free cortisol (UFC) or a 1 mg overnight dexamethasone suppression test. High dose dexamethasone suppression consisted of 2 mg q6h for 48 h or as a single 8 mg overnight dexamethasone suppression test. ACTH levels were measured either by a radioimmunoassay or by immunoradiometric assay.

MRI examinations were performed using a 1.5-T superconducting magnet scanner. Sagittal and coronal T1-weighted images were acquired at 3 mm intervals before and after gadolinium-enhancement. Direct evidence for an intrasellar lesion of a low signal intensity was sought (definite lesion) or in its absence, indirect evidence such as upward bulging of the gland, lateral displacement of the stalk, or an asymmetric sellar floor (equivocal lesion). Imaging studies were independently reviewed by a single radiologist who was blinded to both the results of IPSS and the patient’s histopathologic findings.

Bilateral IPSS was performed after informed consent with simultaneous central and peripheral ACTH measurements obtained before and after administration of ovine CRH 100 µg iv bolus (Ferring Inc.). Catheter placement was verified before and after sampling using gentle injection of contrast. ACTH measurements were taken at 0, 2, 5, 10, and 15 min after CRH injection. In six patients, desmopressin 10 µg iv bolus was used in place of CRH (18) because of an interruption in the supply of CRH. The maximum simultaneous ratio of IPS to peripheral ACTH and the maximum intersinus gradients were then calculated. A central to peripheral gradient greater than or equal to 2.0 at baseline, or 3.0 post-CRH, was considered diagnostic of Cushing’s disease (12). An intersinus gradient greater than or equal to 1.4 was evidence of lateralization. An intersinus gradient less than 1.4 was indicative of either bilateral disease or a midline lesion.

Operative findings, supplemented by histological details and clinical outcomes, served as the gold standard for determining the true location of each patient’s pituitary lesion. Locations were categorized as either right-sided unilateral, left-sided unilateral, or midline/bilateral. Radiographic studies that failed to identify a lesion were classified as unsatisfactory. Similarly, IPSS studies that failed to cannulate both petrosal veins were classified as unsatisfactory. Patients who had both tests available were then classified as having results that were either concordant or discrepant, depending on whether the two tests did or did not demonstrate the same location of pathology.

We determined the accuracy of each diagnostic test by comparing it with intraoperative findings and the results of tissue histopathology. Perfect confirmation (such as when the test indicated a right-sided unilateral lesion and pathology indicated a right-sided unilateral lesion) was classified as "confirmed results". Partial disagreement about location (such as when one test indicated a right-sided unilateral lesion and the other test indicated a midline/bilateral lesion) was classified as "moderately discordant". Substantial disagreement about location (such as when one test result indicated a right-sided unilateral lesion and the other test indicated a left-sided unilateral lesion) was classified as "greatly discordant".

We calculated the frequency of unsatisfactory studies out of the total number of attempted studies. Confidence intervals were calculated using Fleiss’ formula (19). Rates of redundancy between the two tests were calculated using a similar method. Accuracy was calculated by examining the frequency of confirmed results and erroneous results. Additionally, separate analyses examined the accuracy of each test depending on whether results were concordant or discrepant with the alternative test. All P-values were two-tailed and unadjusted for multiple comparisons.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
All patients (n = 37, 84% female, mean age = 36 yr) fulfilled accepted biochemical criteria for the diagnosis of ACTH-dependent Cushing’s syndrome (2). Urinary free cortisol was elevated in most patients (92%), with levels ranging from 220-4190 nmol/day (normal < 220 nmol/day). Seventy percent of patients achieved a reduction of urinary free cortisol (by more than 90%) or plasma cortisol (by more than 50%) after an 8 mg dexamethasone suppression test.

Results of sellar imaging, operative findings, and final pathology are described in Table 1. MRI was performed in 31 patients; the remaining 6 could not undergo MRI because of size constraints and therefore had CT scans. A discrete lesion was definitely visualized by MRI in 18 patients. MRI scanning was equivocal in 6 and negative in 7 other patients. CT scans of the 6 patients for whom MRI was unavailable were normal in 2 cases and equivocal in the remaining 4 cases. Hence, imaging was satisfactory in 28 patients and failed to reveal a lesion in 9 others. No adverse consequences from imaging were observed.

Unilateral pathology was discovered intraoperatively in 27 patients, bilateral lesions were found in 7 patients, and a midline lesion was identified in 1 patient. In 2 other patients, no abnormal tissue was visualized during surgery. The first of these 2 patients underwent a right hemihypophysectomy, performed on the basis of lateralization demonstrated on IPSS; the surgery was curative despite the absence of a demonstrable adenoma on pathological examination. The second of these 2 patients underwent a total hypophysectomy, and pathology demonstrated the presence of diffuse corticotropic hyperplasia.

Twenty-eight patients (76%) had a pituitary corticotropic adenoma proven histologically. Seven patients (19%) had only Crooke’s hyaline change identified in the pituitary; one of the latter had a proven ectopic sphenoid corticotropic adenoma, and the other 6 are assumed to have had pituitary adenomas that were not identified histologically, as they achieved clinical and biochemical remission postoperatively. One patient had nodular hyperplasia (2%), and another had a diffuse form of corticotropic hyperplasia (2%). Interestingly, both cases of hyperplasia presented with a central to peripheral gradient on IPSS, while the former was associated with and the latter without an intersinus gradient. A microadenoma was assumed or proven therefore in 28 patients, of whom 25 were cured by surgery alone. A macroadenoma was present in 7 patients (19%), of whom 4 sustained a remission following transsphenoidal surgery alone. Three other patients with macroadenomas required further therapy (radiation and/or bilateral adrenalectomy).

Neither IPSS nor imaging was ideal for localizing the pituitary lesion. IPSS accurately localized the pituitary lesion in 26 of 37 patients, whereas imaging correctly localized the lesion in 18 of 37 patients (diagnostic accuracy: 70% vs. 49%, P < 0.06). Both studies were not always satisfactory (Table 2). When results were available from both, IPSS and imaging studies were concordant for 67% of patients and discordant for 33% of patients (Table 3). When the two studies were concordant, the results correctly matched the site of the lesion in most patients (Fig. 1). When a discrepancy existed between the two studies, a greater proportion of IPSS results than imaging results correctly matched the site of the lesion (63% vs.13%, P = 0.10). Imaging was negative in 9 patients, of which IPSS correctly localized the site of the lesion in 8 (95% confidence interval 50–99%). Unsuccessful IPS catheterization proved to be highly inaccurate. The procedure accurately localized the lesion in only 1 of 3 patients who underwent unilateral petrosal sampling and contralateral jugular vein sampling. Furthermore, the absence of an intersinus gradient in the two cases of bilateral jugular vein sampling falsely predicted a bilateral lesion.

View larger version (12K): [in this window] [in a new window]   Figure 1. Relative accuracy of IPSS and imaging when both methods were technically successful (n = 24).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

A number of studies have evaluated the role of IPSS in the diagnostic approach to patients with ACTH-dependent Cushing’s syndrome. One study suggested that a central to peripheral gradient in ACTH of greater than 2.0 had a sensitivity of 95% and specificity of 100% (12). By using a cut-off of 3.0 following CRH administration, the sensitivity rose to 100% (12). Subsequent studies have yielded similar results (2, 16, 20, 21, 22). In our study, a central to peripheral ratio was available in 31 patients, of whom 26 (84%) had gradients of greater than 2.0. The largest gradient (111.3) was found in a patient with corticotropic hyperplasia. In four of the five patients who did not demonstrate a central to peripheral gradient, IPSS was technically unsuccessful.

Some studies have correlated IPSS data with surgical findings (2, 3). However, many studies included fewer than a dozen patients. Furthermore, few reports have compared IPSS against histopathology. One review suggested that an intersinus gradient of greater than 1.4 could accurately predict the location of a microadenoma in 70–80% of patients (2). In our study, IPSS accurately located the site of the lesion in 70% of patients. The significance of a negative intersinus gradient has achieved little attention in previous studies; in our study, an intersinus gradient less than 1.4 correlated with a bilateral tumor in three of six patients and diffuse corticotropic hyperplasia in a fourth patient.

There are several major reasons why a large intersinus ACTH gradient may not be found on IPSS despite a known underlying pituitary lesion. First, corticotrophs are primarily located in the median wedge of the adenohypophysis (23), hence, many adenomas arise in this central location and may not be associated with an intersinus gradient. Second, some patients with Cushing’s disease, like two in our series, have primary diffuse or nodular corticotropic hyperplasia without an adenoma. The absence of an ectopic or eutopic source of stimulation by CRH leaves the etiology of such hyperplasia unknown. As noted in our patient with diffuse hyperplasia, however, this can be an additional cause of an absent intersinus gradient on IPSS. Finally, some procedures will be technically impossible because of the marked anatomical variation in the number and size of anastomotic channels between the IPS and vertebral, basilar, and epidural venous plexuses (10).

There are also reasons why a large intersinus ACTH gradient may falsely localize the tumor. For example, Mamelak et al. (24) demonstrated asymmetrical venous drainage in as many as 39% of patients undergoing IPSS. In their study, IPSS correctly lateralized the tumor in 86% of cases with symmetrical drainage, but only 44% of patients with asymmetrical patterns. The authors suggested that routine venography is necessary to correctly interpret results of IPSS (24). Inaccurate results have also been found after previous pituitary surgery. Previous transsphenoidal surgery, however, did not alter the accuracy of IPSS in two of our patients. Earlier treatment with medications that lower serum cortisol levels may eliminate the suppression of nontumorous corticotrophs and attenuate the intersinus gradient. Ectopic location of the lesion may be an additional factor. In our series, a central to peripheral gradient was documented in a patient with an ectopic corticotropic adenoma situated within the sphenoid sinus (25).

Pathology failed to confirm the diagnosis of a corticotropic adenoma in six patients. In patients with cortisol excess, corticotrophs develop accumulation of bundles of intermediate filaments representing low molecular weight cytokeratins. This morphologic alteration, known as Crooke’s hyalinization, is characteristic of nontumorous corticotrophs and is the pathologic hallmark of Cushing’s syndrome. In our six patients, only Crooke’s hyalinization could be identified, indicating the presence of an adenoma that may have been too small to be detected in routine histology or lost during surgical resection but provided pathologic confirmation of the diagnosis of Cushing’s syndrome.

Our study has several limitations, of which three merit emphasis. First, only a small number of patients with Cushing’s disease underwent imaging, IPSS, and definitive surgery. This is a large sample size compared with most other analyses of IPSS, yet is not sufficient for sophisticated statistical analyses. Second, IPSS is typically an arduous procedure and in many cases is conducted only when imaging is inconclusive. This introduces selection bias, which might cause our results to under-estimate the relative accuracy of imaging and over-estimate the relative accuracy of IPSS. Third, IPSS was not performed on all patients as a screening procedure. As a consequence, our study can not provide a precise estimate of the specificity, positive predictive value, or other characteristics of test accuracy.

A great deal of controversy surrounds the question of when to perform IPSS. To justify the procedure, there must be unequivocal evidence of cortisol excess. Indeed, normal subjects or patients who have pseudo-Cushing’s may show an intersinus ACTH or AVP concentration gradient (17, 26). Morbidity from the procedure is low but not negligible. For example, two patients with permanent brainstem injury following IPSS have been reported in the literature (27). The test is expensive and is associated with a total fee of $1125 (Canadian dollars) at our facility including technical and professional components. Our study suggests that a key indication for IPSS is when a patient’s high-dose dexamethasone suppression testing is diagnostic of Cushing’s disease, yet imaging fails to detect an adenoma. More importantly, this procedure should be restricted to centers with a skilled and dedicated team that has expertise in invasive neuro-endocrinology.

Received November 14, 1997.

Accepted April 7, 1998.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Booth, G. L. Articles by Ezzat, S. Search for Related Content PubMed PubMed Citation Articles by Booth, G. L. Articles by Ezzat, S.