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Spoiled Gradient Recalled Acquisition in the Steady State Technique Is Superior to Conventional Postcontrast Spin Echo Technique for Magnetic Resonance Imaging Detection of Adrenocorticotropin-Secreting Pituitary Tumors

Department of Radiology, Warren Grant Magnuson Clinical Center (N.P., N.B., J.D.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development (NICHD) (C.A.S., A.L.), Neurosurgery Branch, National Institute of Neurological Disorders and Stroke (E.H.O.), and Pediatric and Reproductive Endocrinology Branch, NICHD (L.K.N.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Lynnette K. Nieman, M.D., National Institutes of Health, 10 Center Drive, Building 10, Room 9D42, Bethesda, Maryland 20892-1583. E-mail: niemanl{at}nih.gov.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Recent studies show that the standard T1-weighted spin echo (SE) technique for magnetic resonance imaging (MRI) fails to identify 40% of corticotrope adenomas. We hypothesized that the superior soft tissue contrast and thinner sections obtained with spoiled gradient recalled acquisition in the steady state (SPGR) would improve tumor detection. We compared the performance of SE and SPGR MRI in 50 patients (age, 7–67 yr) with surgically confirmed corticotrope adenoma. Coronal SE and SPGR MR images were obtained before and after administration of gadolinium contrast, using a 1.5 T scanner. SE scans were obtained over 5.1 min (12-cm field of view; interleaved sections, 3 mm). SPGR scans were obtained over 3.45 min (12- or 18-cm field of view, contiguous 1- or 2-mm slices). The MRI interpretations of two radiologists were compared with findings at surgical resection. Compared with SE for detection of tumor, SPGR had superior sensitivity (80%; confidence interval, 68–91; vs. 49%; confidence interval, 34–63%), but a higher false positive rate (2% vs. 4%). We recommend the addition of SPGR to SE sequences using pituitary-specific technical parameters to improve the MRI detection of ACTH-secreting pituitary tumors.

	Introduction

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MAGNETIC RESONANCE IMAGING (MRI) has replaced computed tomography (CT) as the method of choice for the evaluation of patients with suspected pituitary pathology (1). Postcontrast MRI scans yield higher detection rates than CT because of superior soft tissue contrast and differential enhancement of the adenomas compared to the normal pituitary. Despite these advances, many pituitary adenomas are not identified by standard T1-weighted spin echo (SE) technique (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Of all pituitary lesions, ACTH-secreting adenomas are particularly challenging because they tend to be small and often exhibit signal and enhancing characteristics similar to those of normal pituitary parenchyma. Other problems hindering the correct identification and localization of these tumors include false positive results caused by computer noise in thin tomographic sections and the presence of nonfunctioning adenomas in as many as 10% of the normal population (15, 16).

Successful treatment of ACTH-secreting adenomas requires accurate diagnosis of Cushing’s disease and exact localization of the tumor. Because imaging has low sensitivity and less than 100% specificity, many institutions have turned to petrosal venous sampling to distinguish a pituitary from an ectopic source of ACTH (17). Although petrosal venous sampling has high diagnostic accuracy, it is an invasive and expensive test and is not widely available. Thus, an improved imaging technique for pituitary disease would be a diagnostic advance.

The spoiled gradient recalled acquisition in the steady state (SPGR) sequence is a relatively new MRI technique characterized by superior soft tissue contrast compared with T1-weighted spin echo (SE) technique. As SPGR can be performed in sections of 1 mm, the spatial resolution of the acquired images is improved (3, 4, 18, 19, 20, 21). We hypothesized that this technique might increase the accuracy of MRI for the detection of ACTH-secreting pituitary microadenomas. To evaluate this possibility, we compared the results of MRI using the SPGR technique with those of the conventional T1-weighted SE technique in 50 patients with surgically proven ACTH-secreting microadenomas.

	Subjects and Methods

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Subjects

We studied 50 consecutive patients with Cushing’s disease. Sixteen children (7–18 yr old) were evaluated for pituitary tumors, and 34 adults (18–67 yr old) were admitted for jugular venous sampling at the Clinical Center of the NIH from December 1997 to August 1999. The pediatric protocol allowed, but the adult protocol excluded, those with known pituitary tumor as judged by MRI examination report sent by the referring physician. Patients were evaluated prospectively after giving informed written consent (adults) or assent and parental permission (children) for participation in each institutional review board-approved protocol. After confirmation of hypercortisolism, biochemical testing for Cushing’s disease included inferior petrosal sinus sampling if the standard T1-weighted SE MRI technique was negative. All patients underwent transsphenoidal surgery for the presumed pituitary adenoma. Histopathological examination of the surgical specimen and postoperative hypocortisolism were used to confirm the diagnosis of an ACTH-secreting adenoma.

Imaging techniques

During preoperative evaluation, MR images were obtained using a 1.5T scanner (Signa, General Electric, Milwaukee, WI). Coronal precontrast T1-weighted spin echo (SE) scans were obtained using the following parameters: repetition time/echo time, 400/9 msec; 192 x 256 matrix; two excitations; 12-cm field of view (FOV); and interleaved sections, 3 mm in thickness without intersection gap. Scan time was 5.10 min. Precontrast SPGR scans were also performed with repetition time/echo time: 9.6/2.3 msec, a 20° flip angle, 160 x 256 matrix, 6 excitations, and 12-cm FOV in 44 patients and 18-cm FOV in 6 patients. Contiguous 1-mm thick coronal slices were obtained in 38 patients, and 2-mm thick slices were obtained in 12 patients. The scan time was approximately 3.45 min. Both the SE and SPGR studies were repeated after iv administration of gadolinium contrast material [0.01 mmol/kg gadopentetate dimeglumine (Magnevist, Berlex Laboratories, Inc., Montville, NJ)]. In 28 patients postcontrast SPGR study preceded, whereas in 22 it immediately followed the postcontrast SE study.

Data capture and analysis

Two experienced radiologists (J.D. and N.P.) reviewed the coronal pre- and postcontrast T1-weighted SE and SPGR images blindly and independently from each other. Radiologists recorded the presence, size, and position (right, left, and central) of any lesion. The findings of each radiologist were compared with the surgical findings by a single neurosurgeon (E.H.O.), which were recorded on a drawing of the pituitary gland showing the size and location of the microadenoma. Sensitivity, specificity, positive predictive value, and diagnostic accuracy of the MR techniques were calculated by comparing the imaging data to the surgical findings, considering the surgical results to represent the gold standard. Ninety-five percent confidence intervals (CI) were calculated for sensitivity and diagnostic accuracy results. Data for tumor size are presented as the mean ± SE. Differences in tumor size judged by the different techniques were compared by paired t tests. P < 0.05 was considered significant.

	Results

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Surgical results

The surgeon located and removed an adenoma at transsphenoidal surgery in 49 of 50 patients. All had histological confirmation of an ACTH-containing tumor or biochemical evidence of remission after surgery. Excluding 3 macroadenomas, the tumor size estimated at surgery was 6.3 ± 0.4 mm (mean ± SE; range, 2–10 mm). In one patient both MRI observers and the surgeon failed to identify a pituitary adenoma. After total hypophysectomy, histological examination of the specimen also did not identify an adenoma. Nevertheless, this patient was hypocortisolemic after surgery.

Imaging results

On precontrast T1-weighted and SPGR images, pituitary microadenomas appeared as small rounded hypointense regions with respect to normal pituitary parenchyma. This abnormality was detected in the minority of the patients: in 6 and 8 patients on the SE images and in 8 and 12 patients on the SPGR images by observers A and B, respectively. There was no evidence of hemorrhage in any of these lesions.

On the postcontrast scans, adenomas appeared as areas of decreased enhancement compared with normal pituitary parenchyma, with a diameter of 2–9 mm. With the SPGR technique some microadenomas showed a small focus of enhancement in the center of the hypoenhancing lesion. This finding was not seen on the SE films.

On the postgadolinium SE scans, observers A and B identified a focal hypoenhancing lesion consistent with adenoma in 22 and 23 of 50 patients (44–46%), respectively. In 20 of these patients both observers correctly identified the adenoma and its location at surgery. In two patients, observer B failed to identify the lesion detected by observer A, and in four patients observer A failed to identify the lesion detected by observer B. Thus, the correct detection rate using both sets of observations was 50%.

Using the postcontrast SPGR scans, the two observers each identified a focal hypoenhancing lesion in 36 patients (72%; Fig. 1). In 34 of these patients both observers correctly identified the adenoma and correctly predicted its location at surgery. In three patients observer A failed to identify the lesion detected by observer B, and in one patient observer B failed to identify the lesion detected by observer A. In one patient although observer A correctly identified and localized the lesion, observer B erroneously identified a focal abnormality on the normal side of the gland. Using the combined data from both observers, the SPGR technique correctly identified tumor in 38 (76%) of 50 patients.

View larger version (98K): [in this window] [in a new window]   Figure 1. MRI scan of a patient with pituitary adenoma. A, Coronal postcontrast SE image of the pituitary shows homogeneous enhancement of the pituitary. No definite adenoma is identified. B, Coronal postcontrast SPGR image of the pituitary demonstrates an abnormal area of diminished enhancement with respect to normal pituitary parenchyma (arrow). This abnormality represents an ACTH-secreting adenoma, which was confirmed at surgery.

The radiological estimates of tumor size, taking both MRI techniques together, were similar to those obtained at surgery, except at the extremes. Although the overall mean size estimates were not significantly different (5.8 ± 0.3 and 5.0 ± 0.3 for MRI vs. 6.3 ± 0.4 for surgery), radiologists overestimated the sizes of tumors that were 5 mm or less at surgery (5.0 ± 0.5 and 5.7 ± 0.5 vs. 3.8 ± 0.2; P < 0.05) and underestimated the sizes of tumors that were 6–10 mm at surgery (5.0 ± 0.5 and 5.9 ± 0.4 vs. 7.5 ± 0.3; P < 0.05).

Although MRI detected a lesion in many patients, there were false negative results of 48–52% for SE and 18–22% for SPGR techniques on the postgadolinium scans. In 24 and 26 patients, no focal lesion was identified using the SE technique by observers B and A, respectively. On the other hand, observers B and A failed to detect the adenoma on SPGR scans in only 9 and 11 patients.

When comparing SPGR to surgical localization of tumor, the two radiologists’ results gave similar sensitivity [77% (CI, 64–89%) and 80% (CI, 68–91%)] and specificity (33% and 20%; CI not calculated because of small number of scans in this category). By contrast, SE had significantly lower sensitivity [46% (CI, 32–60%) and 49% (CI, 34–63%)] with slightly higher specificity (33–50%). The small number of patients with a negative surgical outcome did not allow for statistical comparison of the specificity results. The positive predictive value was similar for both techniques (90–96%), whereas the best diagnostic accuracy from either radiologist was significantly better for SPGR (74%; CI, 61–86%; vs. 48%; CI, 34–61%). When judged together as a single test, the combined sensitivity for both MRI techniques was 82% (CI, 73–94%).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Because of the small size of corticotrope adenomas, conventional SE MRI has not been a useful diagnostic modality, with false negative results of 45–62% (2, 7). In this study we prospectively evaluated 50 patients with clinically suspected Cushing’s disease using SE and SGPR techniques and found that the sensitivity of the SPGR technique for the detection of ACTH-secreting pituitary microadenomas (80%; CI, 68–91%) was superior to that of the SE technique (49%; CI, 34–63%). This improved sensitivity came at the expense of a modest increase in false positive results (SPGR, 8%; SE, 4%).

Our finding of a 49% sensitivity using the SE technique is similar to an overall sensitivity of 59% in previous reports (Table 1) (6, 7, 8, 9, 10, 11, 12, 13, 14). In those studies, as in ours, macroadenomas were always identified by MRI, so that the false negative rate represents undetected microadenomas. The false positive rate in earlier studies from other centers (18%) contrasts with the 4% rate in this study, and the 0% rates in earlier studies from the NIH. We speculate that our criteria for identification of a tumor may be more stringent and may account for the lower false positive rate and the lower sensitivity in the current study compared with others. Thus, local criteria as well as observer experience may contribute to variability in interpretation. The presence of additional silent or hormonally active tumors may also account for "false" positive tumors on MRI. In this setting, the MRI result would correctly identify a tumor, but would falsely consider the tumor to be ACTH secreting. In our series of 660 patients with Cushing’s disease, 2% had a second noncorticotrope tumor at surgical exploration (22). This contrasts with the MR detection of microadenomas in 10% of a healthy population who did not undergo surgical confirmation of the tumor (16). Based on these data, we suspect that false positive identification of tumors on MRI is related primarily to the MR technique and variability in observer experience and criteria and less commonly to the presence of a second tumor.

Although the SPGR technique has been used in various diseases of the brain and other organs, the experience with pituitary lesions is limited. Stadnik et al. (3) evaluated six patients with suspected ACTH-secreting pituitary adenoma and reported a sensitivity of 80% using SPGR. In another study of 76 patients with prolactinoma, SPGR MRI had a high detection rate (75%), but only 15 of these patients had surgical confirmation of the tumor (4). A number of factors may account for the apparent superior sensitivity and diagnostic accuracy of the SPGR compared with the SE technique (19, 20, 21, 23). The SPGR method is characterized by faster acquisition, which minimizes artifacts from motion and vascular pulsation. It also gives better soft tissue contrast. Furthermore, SPGR can be performed with 1-mm thin sections, a theoretical advantage when attempting to detect small pituitary microadenomas. On the other hand, the SPGR technique is known for its inferior signal to noise ratio compared with SE, which may account for the false positive results in this study.

We were surprised to detect pituitary tumors in the adults who were referred after a previously negative pituitary MRI examination obtained in outside institutions. One possibility is that these tumors grew sufficiently in the interval between the two studies to allow detection. This is unlikely, as second scans were usually performed within 5 months, these tumors do not typically increase in size dramatically in that time frame, and tumors were detected at all sizes. Although it was not the object of the study to evaluate images made elsewhere, some were reviewed. We found a great variability in the technical parameters used by the referring centers. Among the inappropriate parameters were large FOV, thick slice thickness (e.g. 5 mm), and scanners less than 1.0T. These informal findings emphasize that successful detection of pituitary adenomas requires the use of imaging parameters optimized for pituitary, and not brain, studies.

Our data raise additional questions that we cannot answer. Because there were few patients in the study with false positive MRI results, we cannot estimate whether there is a true difference in the rate of misdiagnosis using the two techniques. However, as the surgeon explored areas that were abnormal on MRI scan, these abnormalities did not represent a second pituitary tumor. The discrepancy between the MRI and surgical estimation of tumor size is puzzling, in part because the discrepancy was most common at the extremes of tumor size. When surgery is contemplated, these differences between MRI and surgical detection of tumor are not important. However, if MRI is used to plan the location of focused radiotherapy to the pituitary, unwitting use of false positive results may reduce the efficacy of that treatment.

We conclude that SPGR is superior to SE for the detection of ACTH-secreting pituitary tumors. Based on these findings, we suggest that coronal postcontrast SPGR images be added to conventional SE imaging protocols of the pituitary gland. The SE images are complementary to SPGR for the diagnosis of corticotrope tumors and may minimize the false positive findings of the SPGR technique. However, the potentially higher false positive rate with SPGR and the lack of information about SPGR findings in the normal population suggest that imaging alone should not be used to make the diagnosis of Cushing’s disease. Furthermore, the utility of SPGR sequences in the detection of other small non-ACTH-secreting tumors remains to be explored.

	Acknowledgments

 
We thank Margaret Keil, R.N., P.N.P. (Developmental Endocrinology Branch, NICHD, NIH) for her help in organizing imaging studies in pediatric patients with Cushing’s disease.

	Footnotes

 
Abbreviations: CI, Confidence interval; CT, computed tomography; FOV, field of view; MRI, magnetic resonance imaging; SE, spin echo; SPGR, spoiled gradient recalled acquisition in the steady state.

Received September 12, 2002.

Accepted January 2, 2003.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart 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 Patronas, N. Articles by Nieman, L. K. Search for Related Content PubMed PubMed Citation Articles by Patronas, N. Articles by Nieman, L. K.