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Detection of Adrenocorticotropin-Secreting Pituitary Adenomas by Magnetic Resonance Imaging in Children and Adolescents with Cushing Disease

Department of Diagnostic Radiology (N.A.C., N.J.P.), Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; Section on Endocrinology and Genetics (D.B., N.A.C., K.J.G., M.K., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892; Surgical Neurology Branch (E.H.O.), National Institute of Neurological Diseases and Stroke, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Constantine A. Stratakis, Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}mail.nih.gov.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: We recently showed that pre- and postcontrast spoiled gradient-recalled acquisition in the steady-state (SPGR) was superior to conventional pre- and postcontrast T-1 weighted spin echo (SE) acquisition magnetic resonance imaging (MRI) for the diagnostic evaluation of pituitary tumors in adult patients.

Objective: The present investigation assessed the use of SPGR vs. SE-MRI in the diagnostic evaluation of ACTH-secreting tumors in children and adolescents with Cushing disease.

Design: Data were analyzed retrospectively from a series of patients seen over 7 yr (1997–2004).

Setting: The setting for this study was a tertiary care referral center.

Patients: Thirty children with Cushing disease (13 females and 17 males with a mean age of 12 ± 3 yr) were studied.

Interventions and Outcome Measures: Imaging results were compared with surgical and pathological findings and the clinical outcome.

Results: Twenty-eight patients had microadenomas, and two had macroadenomas; the latter were identified by both MRI techniques. Precontrast SE and SPGR-MRI identified four and six of the microadenomas, respectively. Postcontrast SPGR-MRI identified the location of the tumor in 18 of 28 patients, whereas postcontrast SE-MRI identified the location and accurately estimated the size of the tumor in only five patients (P < 0.001).

Conclusions: We conclude that conventional MRI, even with contrast enhancement, mostly failed to identify ACTH-secreting microadenomas in children and adolescents with Cushing disease. Postcontrast SPGR-MRI was superior to SE-MRI and should be used in addition to conventional SE-MRI in the pituitary evaluation of children and adolescents with suspected Cushing disease.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
DETECTION OF ADENOMAS in the pituitary gland by imaging techniques has always been problematic. ACTH-secreting adenomas, in particular, have been proven difficult to localize because these tumors are typically very small (1, 2, 3, 4, 5, 6, 7). Magnetic resonance imaging (MRI) has been considered for the last 2 decades as the imaging method of choice for detection of these tumors (1, 2, 3, 4, 5, 6, 7, 8). Various modifications of MRI techniques have been proposed to improve the rate of tumor detection (7, 9, 10, 11, 12). However, and although MRI sensitivity for pituitary microadenomas varies widely among different investigators, it is generally accepted that these tumors are correctly identified by MRI only in approximately half of the cases (1, 2, 4, 5, 6, 7, 10, 11, 12). One of the main reasons for misdiagnosis is that pituitary tumors and the surrounding normal pituitary gland often exhibit similar signal and enhancing characteristics (2, 7, 11, 12, 13, 14, 15).

Successful treatment of ACTH-secreting adenomas requires accurate diagnosis and exact localization. Because of limitations of imaging (12), many institutions use petrosal sinus sampling (PSS) to distinguish a pituitary from an ectopic source of ACTH. Although PSS has high diagnostic accuracy, it is an invasive and expensive test that is not widely available and carries a finite risk of serious complications. It is also difficult to perform in young children, who have the added risks of sedation or anesthesia. Thus, an improved imaging technique for pituitary tumors in children with Cushing disease would be a significant diagnostic advancement in the work up of these patients.

In a recent pilot study of mostly adult patients, we demonstrated that spoiled gradient-recalled acquisition in the steady-state (SPGR) MRI was superior to the conventional T-1 weighted spin echo (SE) technique in identifying pituitary tumors (11). Because SPGR-MRI can be performed in thin sections of 1 mm thickness, the spatial resolution of the acquired images is substantially improved (16, 17). We hypothesized that this technique might increase the accuracy of MRI for the detection of ACTH-secreting pituitary adenomas and assist in decreasing morbidity associated with transsphenoidal surgery (TSS) for Cushing disease in childhood (18, 19, 20, 21). To evaluate this possibility, we compared the results of MRI using the SPGR technique and the conventional T1-weighted SE technique in 30 children with Cushing disease and surgically proven ACTH-secreting microadenomas.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients and protocol

A total of 30 patients (Table 1) were studied that were admitted consecutively to the National Institutes of Health-Warren Magnuson Clinical Center from January 1997 to August 2003, under investigational protocol 97-CH-0076, after an institutional review board approval and individual patient consents. The mean age was 12 ± 3 yr (mean and SD), and the group consisted of 13 females and 17 males. Cushing syndrome was diagnosed in all patients by standard testing as described elsewhere (22). After confirmation of hypercortisolism, biochemical testing for Cushing disease included PSS, if the standard T1-weighted SE MRI technique was negative. Twenty-four of our patients underwent PSS for confirmation of Cushing disease, using the procedure that we have described elsewhere (23). All patients underwent TSS for identification and excision of a pituitary adenoma. The size and the exact location of the adenoma were identified at surgery using ring curettes of known diameter. Histopathological examination of the surgical specimen and postoperative biochemical evidence of remission of disease (hypocortisolism) confirmed the diagnosis of an ACTH-secreting adenoma.

All MRI scans were performed in a 1.5 T scanner (Signa, General Electric, Milwaukee, WI). Two imaging techniques were used, coronal precontrast T1-weighted SE with repetition time/echo time of 400/9 msec, 192 x 256 matrix, two excitations, 12-cm field of view, and 3-mm-thick interleaved sections without gap; and coronal precontrast SPGR with repetition time/echo time of 9.6/2.3 msec, a 20° flip angle, 160 x 256 matrix, six excitations, and 12-cm field of view. Contiguous 1.5-mm-thick sections were obtained in all patients. The scan time was approximately 3.4 min. Both SE and SPGR studies were repeated after intravenous administration of 0.01 mmol/kg gadopentetate dimeglumine (Magnevist, Berlex Laboratories, Inc., Mintville, NJ).

Data analysis

For the purposes of the present study, all imaging studies were reviewed retrospectively by two radiologists (N.J.P. and N.A.C.) in a blinded fashion, e.g. without knowledge of the surgical outcome and final histology. The radiological interpretation of all images was made first independently by each radiologist; a meeting with the protocol team was then arranged if there was disagreement. A scan was considered positive only if both radiologists agreed either after their first interpretation or their reevaluation after their meeting. Imaging findings were then recorded [presence, size, and position (right, left, central) of any lesion] by the protocol team in a blinded manner. All analyses and comparisons to surgical and histopathologic findings were done by members of the study team that had not participated in the radiological interpretation meetings.

Sensitivity and specificity of both techniques were calculated by comparing the imaging data with the surgical findings, considering the surgical results to represent the gold standard (Table 2). The difference between the sensitivities of both imaging techniques were calculated using a sample test of correlated proportion (Table 3); 95 percent confidence intervals (CI₉₅) were then calculated (24, 25). Differences in tumor size were compared by paired Student’s t tests. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

All tumors detected on the precontrast scans were hypodense; likewise, all lesions identified on the postcontrast scans demonstrated decreased enhancement with respect to the normal pituitary parenchyma regardless of the technique (SE or SPGR) (Fig. 1). When tumors were visible by both techniques, the SPGR technique generally provided a sharper, clearer image (compare Fig. 1, B with C). Two patients had a macroadenoma and were identified by both techniques. Although the largest tumors were identified with both methods, the smaller tumors were only seen with the SPGR technique (Table 1). No tumors found on the SE-MRI were missed by the SPGR scans. No patients with a microadenoma missed on the postcontrast scans had an indirect sign of a pituitary tumor (such as deviation of the stalk or unilateral superior convexity) that could have assisted in the correct diagnosis (2, 9). There was no good correlation between PSS and imaging findings. PSS was performed in 24 of the 30 children; localization of the tumor by PSS was correct in approximately only 50% of the cases, but a larger investigation of PSS data in children is currently ongoing (Batista, D., and C. A. Stratakis, unpublished data).

View larger version (71K): [in this window] [in a new window]   FIG. 1. MRI studies of a patient with a corticotropinoma detected by both SE- and SPGR-MRI in postcontrast studies. This is one of the largest microadenomas encountered in this series. A, Coronal precontrast SE images revealed no abnormality. B, Coronal postcontrast SE images demonstrated a homogeneously hypoenhancing area in the right side of the anterior pituitary lobe. C, Coronal postcontrast SPGR images identified an adenoma in approximately the same location as the enhanced SE scan. Although the adenoma was identified by both studies, the contrast between normal and abnormal tissues is superior on the SPGR images. The tumor location was confirmed at surgery.

No children with ectopic ACTH production were identified. All 30 patients (Table 1) were in remission immediately after TSS, confirmed by undetectable levels of urinary free cortisol postoperatively; however, recently we identified two patients that recurred and in whom histology had identified ACTH-producing cells. These two patients, who also had a negative MRI, were considered as having negative surgical exploration (Table 2), although the surgical report identified a lesion in each case (Table 1). For one of these patients, precontrast SE- and SPGR-MRI studies were not available; in an additional two patients with negative MRIs, the tumor was not found in the first exploration (listed as a negative surgical result in Table 2), but eventually a tumor was found in a second procedure, and its size and location are recorded in Table 1.

In two adolescent patients, a macroadenoma was evident by both SE and SPGR techniques. TSS identified adenomas with vertical diameters measuring 22 and 18 mm, respectively. The remaining patients had microadenomas (size < 1 cm), with nine found on the right, eight on the left side, and 11 near the midline of the gland. Histologic examination did not reveal tissue degeneration, cyst formation, hemorrhage, or necrosis in any of the excised adenomas. The size of the microadenomas varied from 2.5–10 mm; there were no significant differences between the mean size of the tumor at the time of surgery vs. that in postcontrast SPGR-MRI (7.6 ± 0.4 vs. 5.6 ± 0.98, respectively; P = 0.15).

Data analysis: SE- vs. SPGR-MRI

Two patients had a macroadenoma and were identified by both techniques; these patients were excluded from this analysis. When we compared imaging results vs. surgical findings in the remaining patients (Table 2), in the precontrast SE-MRI, 14.2% (four of 28) patients had a microadenoma. In the postcontrast SE-MRI, 18% (five of 28) of the patients had a microadenoma that was identified correctly after taking into account the surgical report. In contrast, in SPGR-MRI, in the precontrast study, 21% (six of 28) of the patients had a microadenoma; after contrast enhancement, SPGR-MRI identified an adenoma in 64% (18 of 28) of the patients.

When the sensitivity was calculated comparing imaging testing vs. the location of the adenoma at surgery (Table 2), the sensitivity for SE-MRI (precontrast T1) was 16% (four of 25; CI₉₅, 5- 40%), and the specificity was 66.7% (two of three; CI₉₅, 13–98%). For the postcontrast SE-MRI, the estimated sensitivity was better at 21% (five of 24; CI₉₅, 8–43%), with a specificity of 50% (two of four; CI₉₅, 9–90%). However, the corresponding values for SPGR-MRI were significantly higher. The sensitivity for precontrast SPGR-MRI was 24% (six of 25; CI₉₅, 8–41%), and specificity was 67% (two of three; CI₉₅, 13–98%). For the postcontrast SPGR MRI, sensitivity was 75% (18 of 24; CI₉₅, 53–89%), and the specificity was 50% (CI₉₅, 9–91%). The difference between the sensitivities of the postcontrast SE-MRI vs. that of the SPGR-MRI was quite significant at 55% (CI₉₅, 36–74%; P = 0.001) (Table 3).

Both techniques had high false-negative rates, but the numbers for SPGR-MRI were significantly better. For SE-MRI (postcontrast), this was 90% (CI₉₅, 68–98%) with a false-positive rate of 28% (CI₉₅, 5–70%). For SPGR-MRI (postcontrast), the values were 75% (CI₉₅, 36–96%) and 10% (CI₉₅, 2–33%), respectively. Finally, the overall probability that postcontrast SE-MRI would be positive in a child with surgically proven Cushing disease was 25% (CI₉₅, 11–45%), whereas the probability that it would be negative was 75% (CI₉₅, 55–86%). On the other hand, for postcontrast SPGR-MRI, the probability that the test would be positive was 71% (C₉₅, 51–86%), whereas the probability that the test would be negative was 29% (CI₉₅, 14–50%). Two representative examples of patients with negative SE-MRIs but positive SPGR-MRIs are shown in Figs. 2 and 3; in the latter, the use of contrast enhancement identified a lesion that was not visible by plain SPGR-MRI, too.

View larger version (114K): [in this window] [in a new window]   FIG. 2. MRI studies of a patient with a corticotropinoma detected only by SPGR-MRI (postcontrast). A, Coronal postcontrast SE-MRI. There is no evidence of adenoma in the pituitary gland. B, Coronal postcontrast SPGR-MRI demonstrates an adenoma, an area of slightly diminished enhancement is identified on the left half of the pituitary. The tumor location was confirmed at surgery.

View larger version (116K): [in this window] [in a new window]   FIG. 3. MRI studies of a patient with a corticotropinoma detected only by SPGR-MRI (postcontrast). A, Coronal precontrast SPGR-MRI. The pituitary enhanced homogeneously, and there was no evidence of an adenoma in the anterior lobe of the gland. B, Coronal postcontrast SPGR-MRI showed an adenoma, as an inhomogeneously hypoenhancing area on the right side of the adenohypophysis. The tumor location was confirmed at surgery.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

Cushing disease is extraordinarily rare in children and adolescents (19, 20, 21). The majority of pediatric patients with Cushing disease have small microadenomas as the cause of their disease; in addition, pituitary incidentalomas are rare in children (20, 21, 22, 26). The present study is the largest that specifically evaluated the use of any type of MRI for detection of pituitary corticotropinomas in children, but we also evaluated a new modality, SPGR-MRI. The detection rate of 64% with a sensitivity of 75% represents a significant improvement over conventional imaging techniques that are currently in use.

The low detection rate of these tumors in children by conventional imaging, which in the present study was at approximately 20%, was less than half of that reported in adults (1, 7, 11). Possible explanations for this difference are the relatively smaller size of ACTH-secreting adenomas in children (22) and the absence of tissue degeneration, necrosis, or cyst formation in pituitary adenomas of younger patients (24). These tissue changes provide additional elements of separation from adjacent normal tissue, which make the presence of an adenoma more obvious upon radiological studies (2, 5, 6).

A number of factors may account for the apparent superior performance of the SPGR compared with the SE technique (7, 8, 9, 10, 11, 12). The increased soft tissue contrast with SPGR is well-acknowledged; with it, images can be obtained with 1.5-mm-thin sections (16, 17) (Fig. 1). SE imaging, on the other hand, is usually obtained with 3-mm thickness, and averaging of different tissues can obscure smaller pituitary microadenomas (7, 8, 9, 10, 11). The main drawback of the SPGR technique is its inferior signal to noise ratio compared with SE-MRI (11, 16, 17). In this study, we doubled the number of excitations from three to six to alleviate this problem. In doing so, the specificity of the findings was improved, whereas the scan time was still shorter than that of the SE technique, thus, minimizing motion artifacts that can be encountered with prolonged scanning.

As was the case in adult patients (11), we were surprised to detect pituitary tumors in pediatric patients who were referred after a previously negative MRI had been obtained elsewhere. Is it possible that these tumors grew sufficiently in the interval between the two studies to allow detection? Although this is a possibility, it is unlikely because our imaging usually took place within 6 months from the previous study. First, pituitary tumors typically do not increase in size over an interval of only a few months. Second, the tumors that were detected by SPGR-MRI in the course of our study, after a recent negative MRI elsewhere, covered the same range of sizes as other corticotropinomas that have been reported in the literature (1, 2, 11); a recent size increase would suggest that the newly detectable tumors would be, on average, of smaller size. Third, in the previous study (11), we reviewed films obtained at other institutions and found a great variability in the technical aspects of the scanning procedure and, consequently, the quality of imaging (11). Optimal detection of pituitary adenomas requires the use of imaging techniques developed for pituitary studies, not brain; it is generally better if these studies, especially in children, are obtained at specialized, tertiary referral centers for Cushing disease (26).

The difference in the rate of detection using the two techniques was not statistically different in the pediatric population, whereas in adult patients, there were too few patients with false-positive findings to make a meaningful comparison (11). The false-positive rate in pediatric patients was 28% (CI₉₅, 5–70%) and 10% (CI₉₅, 2–33%) for the SE- and SPGR-MRI (postcontrast), respectively. This is comparable with the 18–20% rates reported by other centers for conventional pituitary MRI but contrasts with the 4% rate found in the study of adult patients (11) and the 0% rates in earlier studies from the National Institutes of Health (1). It is possible, therefore, that SPGR-MRI, at least in children, increases the chances of falsely detecting a pituitary tumor. From the surgical and pathological findings, we know that MRI-detected abnormalities did not represent additional pituitary lesions, which in some cases of Cushing disease may coexist (27).

The surgical cure rate for Cushing disease is 80–90% when MRI localizes a tumor but drops to 50–70% when the lesion cannot be demonstrated upon preoperative imaging (28, 29, 30, 31). Because in a patient with endocrine testing consistent with Cushing disease a positive MRI almost always indicates the site of the ACTH-secreting adenoma, as it did in the current series, and because pituitary exploration with multiple incisions in the gland can produce hypopituitarism in some patients, our surgeon (E.H.O.) begins exploration for the adenoma based on the site of the positive MRI. If a tumor is found there, the tumor is removed, and no further exploration of the gland is performed. Thus, the correct localization of the tumor on MRI not only provides higher remission rates, but also, by limiting the exploration of the pituitary gland that is necessary, it may reduce the incidence of postoperative complications, such as cerebrospinal fluid leak and hypopituitarism. Suggestive localization on MRI guides the surgeon during TSS, even if the imaging study was not definitive (32).

We conclude that coronal postcontrast SPGR images should be added to conventional SE imaging protocols of the pituitary gland. SE images are complementary to SPGR images for the diagnosis of corticotropinomas, and both techniques should be used for the investigation of the pituitary gland in all patients with Cushing syndrome. Although imaging alone cannot establish the diagnosis of Cushing disease in patients with Cushing syndrome, it plays a crucial supporting role to diagnostic endocrine testing.

	Acknowledgments

 
We thank, first, our patients who participated in National Institute of Child Health and Human Development 97-CH0076 investigational protocol (Principal Investigator, C.A.S.) and, second, Dr. Alicia Y. Toledano (Center for Statistical Sciences at Brown University, Providence, RI) for her review of our statistical analysis and presentation.

	Footnotes

 
Present address for N.A.C.: Department of Radiology, Medical School, Democritos University of Thrace, 68100 Alexandroupolis, Greece.

First Published Online June 7, 2005

¹ D.B. and N.A.C. have contributed equally to this work and are thus sharing first authorship.

Abbreviations: CI₉₅, 95% Confidence interval; MRI, magnetic resonance imaging; PSS, petrosal sinus sampling; SE, spin echo; SPGR, spoiled gradient-recalled acquisition in the steady-state; TSS, transsphenoidal surgery.

Received September 7, 2004.

Accepted May 31, 2005.

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