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Relative Contributions of Inferior Petrosal Sinus Sampling and Pituitary Imaging in the Investigation of Children and Adolescents with ACTH-Dependent Cushing’s Syndrome

Departments of Endocrinology (A.L., A.B.G., A.H., G.M.B., M.O.S.), Radiology (J.E.D., J.E.), Radiotherapy (P.N.P.), and Neurosurgery (F.A.), St. Bartholomew’s and Royal London School of Medicine and Dentistry, London, United Kingdom EC1 7BE

Address all correspondence and requests for reprints to: Prof. Martin O. Savage, Pediatric Endocrinology Section, Department of Endocrinology, St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE. E-mail: m.o.savage{at}mds.qmw.ac.uk

Abstract

Selective transsphenoidal microadenomectomy is the first line treatment of childhood Cushing’s disease, with accurate preoperative localization of the corticotroph adenoma an important step in its investigation. Inferior petrosal sinus sampling (IPSS) for ACTH after CRH stimulation is a recognized investigation in adults, but there are few data in the pediatric age range. We report the relative contributions of IPSS and pituitary imaging in 11 patients, aged 10.7–18.8 yr, presenting with Cushing’s disease. All underwent transsphenoidal surgery (TSS).

IPSS was performed without complication. Sampling was from the inferior petrosal sinuses in 7 patients and the high jugular veins in 4 (patients 2, 4, 5, and 10). The central to peripheral ACTH (IPS/P) ratios were more than 2 (2.5–157.2) in 10 of 11 patients, confirming central ACTH secretion. In 3 patients with high jugular sampling, IPS/P ratio ranged from 2.5–21.1. In the fourth patient with high jugular sampling (IPS/P ratio, 0.95), a central adenoma was identified surgically, and the patient was cured after TSS. The interpetrosal sinus ACTH gradient (IPSG) was more than 1.4 (2.1–20.8) in 10 patients, indicating lateralization of ACTH secretion to the right side in 6 patients and to the left in 4. IPSG ratios were 2.1–8.5 in 3 patients with high jugular sampling. Pituitary imaging (computed tomography and or magnetic resonance imaging) was reported to identify an adenoma in 5 of 11 patients.

At operation a tumor was visualized by the same surgeon in all 11 cases. In 9 patients with lateralization on IPSS, the correct side of the tumor was confirmed at surgery. In a 10th patient with a negative IPSG, a central tumor was present. Thus, IPSS gave a 91% prediction of correct tumor localization. In only 1 of 5 patients with an adenoma reported on pituitary imaging was this localization confirmed at surgery, a prediction rate of only 9%. After TSS, 8 patients were cured, 1 was in remission, and 2 required pituitary irradiation. In 73% of patients undergoing IPSS, localization of the adenoma was followed by surgical cure or remission.

Pituitary scanning was therefore relatively unhelpful in localizing the adenoma. In experienced hands, however, IPSS was feasible in this age group, safe, and strongly predictive of the site of the adenoma, leading to a high rate of successful surgical outcome.

ACTH-DEPENDENT CUSHING’S syndrome is a rare, but important, cause of severe morbidity in childhood and adolescence (1, 2, 3), and presents an important diagnostic and therapeutic challenge to the pediatric endocrinologist. There is now general agreement that the first line therapy for Cushing’s disease is transsphenoidal surgery (TSS) to remove the ACTH-secreting corticotroph adenoma (1, 2, 3, 4, 5).

Since the establishment of TSS for Cushing’s disease, preoperative investigations have attempted to identify the site of ACTH secretion, firstly to differentiate a central from an ectopic source and secondly to facilitate the pituitary surgery. The two principal preoperative investigations suggested in this respect are high resolution pituitary imaging using computed tomography (CT) or magnetic resonance imaging (MRI) (6, 7, 8) and bilateral simultaneous inferior petrosal sinus (IPS) catheterization with sampling for ACTH (IPSS) (2, 8, 9, 10, 11).

Both investigations have become routine in the investigation of adult patients (8, 12); however, experience in children and adolescents, particularly with IPSS, is less extensive. We report an analysis of the relative contributions of pituitary imaging and IPSS, which we have performed since 1986, in the investigation of childhood ACTH-dependent Cushing’s syndrome and relate it to the operative findings and long-term therapeutic outcome.

Subjects and Methods

Eleven patients, six girls and five boys (mean age, 12.3 ± 3.9 yr; range, 10.6–18.8 yr), with ACTH-dependent Cushing’s syndrome underwent simultaneous bilateral IPSS between 1986 and 2000. Four of these patients were reported previously (3) without analysis of IPSS and surgical outcome. IPSS was not attempted for technical reasons in one patient, aged 6 yr, and two patients, aged 7 yr. Pituitary imaging was performed in all patients, consisting of CT scan alone in two, both CT and MRI scanning in four, and MRI alone in five.

Diagnosis of Cushing’s disease

The diagnosis of Cushing’s disease was based on the following biochemical criteria: hypercortisolemia, confirmed by loss of serum cortisol circadian rhythm, and failure of serum cortisol to suppress to less than 50 nmol/liter on a low dose dexamethasone suppression test (8). The diagnosis of Cushing’s disease was supported by suppression of serum cortisol to more than 50% of basal values in a high dose dexamethasone suppression test (8) in all patients plus an exaggerated serum cortisol increase of more than 20%, compared with baseline values, during a CRH stimulation test (3).

Protocol for IPSS

The catheterization was performed without sedation or systemic anesthesia in each case by the same radiologist (J.E.D.) based on the technique described by Oldfield (12). Informed written consent was obtained from the parents of all children before the procedure. Under local anesthesia, two 7F angiographic sheaths were first introduced into the femoral vein by the Seldinger technique, then two 6F multipurpose-shaped catheters were inserted through these sheaths; one of the sheaths was also used for peripheral vein sampling. Systemic anticoagulation was induced with an iv bolus injection of 50 IU/kg heparin after vascular access had been obtained. Under radiographic guidance, the catheters were advanced over a guide wire through the right heart into both low internal jugular veins. Blood was then aspirated over 2 min simultaneously from both catheters and one of the femoral sheaths. The same procedure was repeated after the catheters were advanced into the high internal jugular veins. The position of the catheters in the IPS was checked by injecting 1–2 ml nonionic contrast medium before and again after sampling. If the IPS could not be selectively catheterized, the tips of the catheters were positioned high in the internal jugular veins at the level of the tip of the mastoid process. The venous drainage pattern was not assessed by image intensification in these patients.

After optimal catheter placement, blood samples for ACTH were taken before and at 3–5, 8–10, and 13–15 min after bolus iv human sequence CRH (1 µg/kg; h-CRH, Ferring Pharmaceuticals Ltd., Malmo, Sweden) into a vein in the arm. At the end of the procedure, hemostasis was achieved by manual compression. The duration of the procedure was 60–90 min.

Interpretation of data from IPSS

Evidence for central ACTH secretion. A central to peripheral (IPS/P) ACTH ratio, i.e. the highest right or left IPS value after CRH, compared with the level simultaneously measured from the peripheral vein sample, was taken as indicative of pituitary ACTH secretion. An IPS/P ratio more than 2 was strongly suggestive of pituitary secretion, i.e. Cushing’s disease (8).

Evidence of lateralization of ACTH secretion. An IPSG of more than 1.4, between the ACTH values after CRH treatment, was taken as suggestive of lateralization of the pituitary adenoma (8, 9).

Assay for ACTH

Plasma ACTH concentrations were determined by RIA (11).

Pituitary imaging

CT scanning was performed after administration of iv contrast. One-millimeter axial slices were acquired through the pituitary fossa, and images were reconstructed in the sagittal and coronal planes.

MRI was performed at 1.5 Tesla. T1-weighted sequences were acquired in the sagittal and coronal planes with a 3-mm slice thickness. After gadolinium administration, two further acquisitions were made in the coronal plane: a dynamic sequence within 60 sec of contrast and subsequently a gradient-echo volume acquisition, which was reconstructed in sagittal and axial planes.

Operative findings

The 11 patients in this series, with the addition of those 3 judged too young for IPSS, were all the pediatric patients who had TSS for Cushing’s disease during this period. Each patient underwent TSS by the same surgeon (F.A.), who had knowledge of the results of the IPSS. Operative findings of the localization of the corticotroph adenoma are based on detailed operation notes recorded at the time of surgery. The operative findings and outcome of TSS were considered the reference for localization of the pituitary adenoma.

Therapeutic outcome

Postoperative biochemical assessment was performed in the first week after TSS, having discontinued hydrocortisone assessment for at least 72 h. Therapeutic outcome was classified as cure, i.e. postoperative serum cortisol less than 50 nmol/liter and absence of recurrence; remission, i.e. postoperative serum cortisol less than 300 nmol/liter and absence of recurrence; or persisting hypercortisolemia, requiring postoperative pituitary irradiation (3). Long-term follow-up ranged from 0.5–14 yr (median, 6 yr).

Results

Details of patients, pituitary imaging, IPSS, surgical findings, and therapeutic outcome are shown in Table 1.

Bilateral IPSS was achieved in seven patients, and high jugular sampling in four. There was no relationship between age and the success of petrosal sinus catheterization. There were no complications.

Confirmation of central ACTH secretion

In 10 patients, peak IPS/P ratios after CRH were more than 2 (range, 2.5–157.2), confirming central ACTH secretion (Table 2). In 1 patient (no. 2), in whom samples were obtained from the high internal jugular veins, the negative IPS/P ratio of less than 2 (0.95) could not be interpreted as lack of central ACTH secretion or the IPSG value of 1.3 as lack of lateralization because of the positions of the catheters. As this patient had biochemical investigations consistent with Cushing’s disease, transsphenoidal surgery was performed, and a central adenoma was identified, removed, and confirmed histologically.

In 10 patients, the IPSG was more than 1.4 (range, 2.1–10.5) after CRH, indicating apparent lateralization of ACTH secretion, which was identified on the right side in 6 patients and on the left in 4 patients (Table 1). Lateralization was demonstrated in all 7 patients having IPSS and in 3 of 4 patients having high jugular sampling. In 1 patient (patient 2), high jugular sampling did not show positive lateralization (ratio, 1.3); at surgery, this patient was found to have a central adenoma.

Results of pituitary imaging

Pituitary imaging using CT or MRI was consistent with the presence of an adenoma in 5 of the 11 cases, 4 on the right side and 1 on the left. In all cases radiological reporting was performed before the IPSS, and the radiologist was blinded to the results of IPSS.

Operative and histological findings

A distinct tumor was visualized during surgery in each of the 11 cases; 6 were on the right side, 3 on the left, and 2 in the central part of the gland. In 5 patients, the adenoma was confirmed histologically. In 6 patients, tissue was not available for histological analysis.

Concordance between the findings of ACTH sampling or pituitary imaging and at surgery

In 9 of 10 patients who had lateralization of the tumor on ACTH sampling, the correct lateralization was confirmed at surgery. A 10th patient (no. 2), who had a negative IPSG, was found to have a central tumor at surgery. The 11th patient with catheter lateralization (IPSG, 7.1) also had a central tumor. Thus, ACTH sampling gave an 91% prediction of correct tumor localization (Table 3).

Therapeutic outcome

Eight patients were cured after transsphenoidal surgery, one was in remission, and one patient had persisting hypercortisolemia and required pituitary irradiation. In seven of the eight who were cured, ACTH sampling correctly predicted the site of the adenoma. In the eighth, there was no lateralization on IPSS (IPSG, 1.3), and a central tumor was identified and removed. In only one case did the pituitary imaging correctly predict the site of an adenoma, which was then successfully removed at surgery.

Discussion

After the age of 7 yr, Cushing’s disease is the most common form of Cushing’s syndrome in childhood (2, 3, 13, 14). The accurate diagnosis of an ACTH-secreting pituitary adenoma in children is important and is directly related to the high rate of cure after transsphenoidal surgery, which in the most experienced hands may approach or exceed 70% (2, 3, 5, 15, 16, 17). Although IPSS is now accepted as part of the investigation protocol of ACTH-dependent Cushing’s syndrome in adults (8), its use in children is practiced in only a small number of specialist centers.

Since 1986 we have routinely considered performing IPSS in children with ACTH-dependent Cushing’s syndrome. In three of our patients below 8 yr of age it was not performed because of the potential technical difficulties of catheterization. We have had no complications from this procedure. In children, it has been suggested that IPSS can be hazardous, expensive, and noncontributory and should be reserved for patients with Cushing’s syndrome when the source of ACTH secretion remains unknown after standard investigations (17, 18).

In our view, the principal goal of IPSS in childhood is to confirm the diagnosis of pituitary-dependent disease and help to localize the microadenoma within the pituitary. We used an IPS/P gradient cut-off value of more than 2.0 after CRH administration to indicate a central origin of ACTH secretion. This is based on the finding in our adult Cushing’s syndrome series that no patient with a gradient of more than 2.0 had ectopic ACTH syndrome (19). This is lower that the values of 3.0 (9) and 2.5 (2) reported by the NIH. Using this cut-off, our results showed that IPSS confirmed central ACTH secretion in 10 of 11 cases.

Ectopic ACTH secretion is extremely rare in the pediatric age range. Of 306 cases of pediatric and adult Cushing’s syndrome investigated at St. Bartholomew’s Hospital between 1969 and 1997, 32 had ectopic ACTH syndrome, of whom only 1 was of pediatric age (8). This child presented at age 11 yr elsewhere and was confirmed at our center at age 18 yr to have an ACTH-secreting bronchial carcinoid tumor (3). As ACTH-dependent Cushing’s syndrome is therefore highly likely to be of central origin, the ability of IPSS to potentially lateralize pituitary ACTH secretion is very relevant to surgical exploration and, as we have shown, to subsequent long-term outcome.

Our study demonstrates that in experienced hands IPSS is feasible and can be performed without complications in children as well as adolescents. Our youngest patient was 10.6 yr, although children as young as 5 yr have been successfully studied (2). As the goal of pituitary surgery is the selective complete removal of adenomatous tissue with sparing of the normal pituitary gland, preoperative localization of the adenoma is an important step in the investigation and treatment of Cushing’s disease. We have demonstrated that high jugular sampling for ACTH gave positive information on both the central source of ACTH, as previously reported (20), and localization of the adenoma.

The results of IPSS in our patients were highly informative and gave a high prediction of the site of the tumor, which was directly related to surgical result and overall therapeutic outcome. The accuracy of lateralization results after CRH treatment was 78% in the large meta-analysis of published data (8) and 84% in our adult series (19). This is close to the 76% value reported by the NIH group (2). Our own group of pediatric patients is smaller, and in a larger series, the percent lateralization would be likely to decrease from the current 91%.

Cavernous sinus venous angiography was not performed as part of this investigation in our patients. Interpretation of IPSS lateralization data can be satisfactorily performed (8) without cavernous sinus venous angiography, which would lengthen the procedure and potentially increase the risk of complications. The timing of the ACTH sampling differs slightly from those reported by the NIH. The 5 min sample after CRH administration has been shown in adult patients to be the most critical value for IPS/P and IPSG analysis (19).

Most ACTH-secreting corticotroph tumors are microadenomas, and in childhood pituitary imaging, even the most modern technology may fail to detect a tumor (2, 3, 5, 17, 18). Indeed, we found that imaging was relatively unhelpful, failing to identify a corticotroph adenoma in most cases. By contrast, in a relatively small number of patients, IPSS was feasible, free of complications, and highly successful in correctly lateralizing the tumor within the pituitary fossa, proving to be of more benefit than conventional imaging. We believe that in experienced centers, IPSS should always be considered in the investigation of ACTH-dependent Cushing’s syndrome in the pediatric age group.

Acknowledgments

Footnotes

Abbreviations: CT, Computed tomography; IPSG, interpetrosal sinus ACTH gradient; IPS/P ratio, central to peripheral ACTH ratio; IPSS, inferior petrosal sinus sampling; MRI, magnetic resonance imaging; TSS, transsphenoidal surgery.

Received February 22, 2001.

Accepted August 28, 2001.

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