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From the Clinical Research Centers |
Division of Endocrinology (K.E.G., M.H.S., D.M.C., D.L.L.), Department of Radiology and Dotter Interventional Institute (G.M.N., S.L.B.), and Department of Neurosurgery (O.R.O., S.L.B.), Oregon Health Sciences University, Portland, Oregon 97201
Address all correspondence and requests for reprints to: Kathryn E. Graham, M.D., Division of Endocrinology L-607, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201.
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Abstract |
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Ninety-three consecutive patients with ACTH-dependent Cushing’s syndrome were prospectively studied with bilateral, simultaneous CSS before and after oCRH stimulation. Prediction of a pituitary or ectopic ACTH source was based on cavernous/peripheral plasma ACTH ratios. Intrapituitary tumor location was predicted based on lateralization (side to side) ACTH ratios. These predictions were compared to surgical outcome in the 70 patients who had surgically proven pituitary (n = 65) or ectopic (n = 5) disease.
CSS distinguished pituitary Cushing’s disease from the ectopic ACTH syndrome in 93% of patients with proven tumors before oCRH administration and in 100% of patients with proven tumors after oCRH. It was as safe and efficacious as published IPSS results. CSS accurately predicted the intrapituitary lateralization of the tumor in 83% of all patients and 89% of those patients with good catheter position and symmetric venous flow.
CSS is as safe and accurate as IPSS for distinguishing patients with pituitary Cushing’s disease from those with the ectopic ACTH syndrome. In addition, CSS appears to be superior to IPSS for predicting intrapituitary tumor lateralization.
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Introduction |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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10% of cases)
from this more common etiology. Although patients with the ectopic ACTH
syndrome tend to have a more severe syndrome, with rapid onset of
symptoms and higher cortisol and ACTH levels, there is considerable
overlap in the clinical presentation of this syndrome (particularly
when it is occult) and Cushing’s disease (2). Noninvasive laboratory
studies, including low and high dose dexamethasone suppression tests
(3, 4), metyrapone stimulation (5), and peripheral ovine CRH (oCRH)
stimulation tests (6), are often used to distinguish pituitary from
ectopic disease. However, each fails to accurately distinguish these
two etiologies in 10–30% of cases (3, 4, 5, 6). Further, imaging procedures
are limited by the significant incidence (10–15%) of pituitary
incidentalomas (7), the low sensitivity (<50%) of magnetic resonance
imaging (MRI) for ACTH-secreting pituitary microadenomas (8), and the
difficulty in locating small ectopic ACTH-secreting carcinoid tumors
(2). Due to these limitations in noninvasive biochemical testing and imaging procedures, inferior petrosal sinus sampling (IPSS) was developed (9) and has been shown to be highly accurate in distinguishing pituitary vs. ectopic sources of ACTH (10). However, for optimal performance, IPSS requires the administration of oCRH, which has not been commercially available until recently. Despite these advances, the prediction of exact tumor location within the pituitary gland with IPSS has been suboptimal (9, 11). The cavernous sinuses, which collect blood from the pituitary gland before emptying into the inferior petrosal sinuses, have higher ACTH levels (12) and therefore might allow sampling without the need for oCRH and provide more accurate intrapituitary tumor lateralization information. However, it is technically more difficult to advance catheters into the cavernous sinuses, which could affect success rates. Previous studies of cavernous sinus sampling (CSS) have been limited by technical factors (12, 13) and have included only small numbers of patients (11, 12, 13), and only one patient with the ectopic ACTH syndrome has been evaluated in any of these studies (13). For the first time, we report the use of bilateral cavernous sinus sampling before and after oCRH stimulation in a large series of patients to address the following questions. 1) Is CSS feasible, safe and as efficacious as IPSS? 2) Can CSS eliminate the need for oCRH stimulation? 3) Can CSS provide more accurate information than IPSS about the location of adenomas within the pituitary gland to guide surgical therapy?
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Experimental Subjects |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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The use of oCRH, an investigational drug at the time of the
study, was approved by the OHSU institutional review board, and
written, informed consent was obtained from all patients. A peripheral
iv catheter was established in a forearm vein. Using sterile technique,
7 Fr. Brite or 6 Fr. cordis envoy catheters were inserted
percutaneously over 0.035-in. Bentson guide wires into the right and
left femoral veins. The catheters were advanced through the inferior
and superior vena cavas, internal jugular veins, and jugular bulbs and
into the right and left petrosal sinuses using fluoroscopy. Catheters
were flushed with heparin, but patients were not systemically
heparinized. Tracker 18 Hi Flow catheters (Target Therapeutics,
Fremont, CA) were inserted through the guide catheters and advanced to
the right and left cavernous sinuses. The location of the catheters was
confirmed in each patient before and after the sampling procedure by
venography using slow injection of approximately 1 mL contrast. An
example of catheter position is demonstrated in the skull radiograph
shown in Fig. 1
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Venograms were analyzed independently by a neuroradiologist (G.M.N.) without knowledge of the CSS or surgical results for the quality of catheter position and the presence of any cavernous sinus anatomic and/or venous flow abnormalities. Flow symmetry was determined by rating the degree of opacification of the inferior petrosal sinus and jugular vein on each side after contrast injection.
Assay of ACTH levels
ACTH levels were measured in all samples by immunochemiluminescent assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a normal range of 9–52 pg/mL (2–11 pmol/L), a sensitivity of 2 pg/mL (0.4 pmol/L), and intra- and interassay coefficients of variance below 10%. All samples from a single patient were run in the same assay.
Cavernous/peripheral and lateralization gradient ratios
Cavernous/peripheral ACTH gradients were calculated at each time point as simple mathematic ratios. For the purposes of clinical decision-making, pre-oCRH stimulation ratios of 2.0 or more and/or post-oCRH stimulation ratios of 3.0 or more were defined as indicating a pituitary source of ACTH based on previously published findings for IPSS (10). All patients in whom any cavernous/peripheral ratio indicated a pituitary source were advised to undergo TSS, either at OHSU or at the referral hospital. In patients in whom pituitary tumors were proven by TSS (see criteria below), lateralization ratios were calculated by comparing ACTH levels in the right and left cavernous sinuses for each time point. For clinical purposes, a lateralization ratio of 1.4 or more was used to predict the side of a pituitary adenoma based on previously published findings for IPSS (10).
Surgical classification
A pituitary source of ACTH was confirmed if a tumor was found during TSS with histology showing an adenoma or hyperplasia (rare, seen in only one patient) and immunohistochemistry revealed ACTH staining. In cases where no tumor was found, a pituitary source was considered proven if the patient was cured of hypercortisolism by TSS [second postoperative day morning serum cortisol <2 µg/dL (<55 nmol/L) and/or normalization of 24-h UFC]. This additional criteria for proof of a pituitary source is based on the experience that these tumors are typically semisolid, soft, or milky in consistency and are often not recovered for pathological analysis (17). The location of the adenoma, if found, was noted by the surgeon to be right, left, or midline.
The ectopic ACTH syndrome was proven in patients who underwent resection of an extrapituitary tumor with immunostaining for ACTH.
Statistical analysis
The patient groups were compared with regard to demographic data by the Kruskal-Wallis test for nonparametric data. Post-hoc analysis used the Tukey-Kramer highest significant difference test. Diagnostic performance was assessed for the ability of CSS to distinguish pituitary from ectopic ACTH sources and to predict lateralization with standard formulas for sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Cavernous/peripheral and lateralization ratios were evaluated by receiver-operator characteristic (ROC) curves to determine optimal diagnostic cut-offs. Statistical analysis was performed using SPSS computer software (SPSS, Inc., Chicago, IL).
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Results |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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CSS was safely performed in all patients with no complications. In
86 patients (92%), both cavernous sinuses were successfully
cannulated. In 7 patients, the cavernous sinus was not able to be
cannulated on 1 side. However, in all patients the inferior petrosal
sinus was cannulated. Outcomes for all patients are shown in Fig. 2. Of the 93 patients referred, two were
subsequently believed to have pseudo-Cushing’s syndrome with mild
hypercortisolism based on clinical follow-up, and 1 was
normocortisolemic (with the original diagnosis of Cushing’s syndrome
confounded by a laboratory error in urinary cortisol measurement).
These patients had no further treatment after CSS and therefore were
excluded from further analysis. Of the remaining 90 patients, 81 were
predicted by CSS to have a pituitary source of ACTH (Predicted
Pituitary in Fig. 2) based on the criteria for cavernous/peripheral
ratios described above and were advised to have transsphenoidal
surgery. Seventy-six of the 81 Predicted Pituitary patients underwent
TSS (TSS in Fig. 2). A pituitary source of ACTH was confirmed in 65 of
76 patients who underwent TSS (Pituitary Proven) by 1) demonstration of
a pituitary tumor during TSS with histological evidence of an
ACTH-staining adenoma or hyperplasia (n = 33), or 2) cure of the
patient’s hypercortisolism by TSS, proving a pituitary source for the
ACTH even if no tumor was identified by histology (n = 55; note
that some patients met both criteria).
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Eleven patients underwent TSS but did not meet criteria for proving a pituitary tumor. Typical gross tumor was found in seven, but histology did not reveal adenomatous tissue; one of these patients had an empty sella, suggesting pituitary pathology and potentially making surgical exploration more difficult. No tumor was seen in the other four patients, including a second patient with an empty sella. One of these four patients had Cushing’s disease cured by TSS 6 yr earlier and developed recurrent symptoms. None of these 11 patients were cured by TSS. They have been followed for a mean of 37 months (range, 10–64), and in that time, no ectopic tumor has been found. Based on these observations, these patients also most likely have Cushing’s disease; however, we cannot prove this by our rigorous criteria. Therefore, they are classified as Pituitary Suspect together with the five patients who did not undergo TSS and analyzed with regard to demographic data only.
CSS predicted an ectopic source of ACTH in 9 of the 90 patients with
Cushing’s syndrome (Predicted Ectopic in Fig. 2
). The ectopic ACTH
syndrome was proven in 5 of these 9 patients by demonstration of
ACTH-staining bronchial carcinoid tumors (Ectopic Proven). In the
remaining 4 patients, an ectopic source of ACTH has not yet been
located. One patient subsequently died of a metastatic pancreatic
tumor; tissue was inadequate to evaluate ACTH staining. In 3 other
patients, no tumor was found despite multiple imaging procedures in
mean follow-up of 42 months (range, 23–56). These 4 patients, in whom
an ectopic tumor could not be confirmed, comprise the Ectopic Suspect
group for demographic analysis only.
Demographics and noninvasive biochemical evaluation
Evaluation of demographic and baseline laboratory data is shown in
Table 1 and Fig. 3, with all 90 patients with Cushing’s
syndrome assigned to 1 of the 4 groups described above (the normal
patient and patients with pseudo-Cushing’s syndrome are not included).
There were no differences between the groups with regard to age
(P = 0.70) or gender (P = 0.21; data
not shown for either) or random serum cortisol (Fig. 3, upper
left; P = 0.053). Statistical differences were
found among the groups for morning serum cortisol (Ectopic Proven
higher than Pituitary Suspect, P = 0.027), 24-h UFC
(P = 0.007, but no difference detected by
post-hoc analysis), and plasma ACTH levels (Ectopic Suspect
higher than either pituitary group and Ectopic Proven higher than
Pituitary Suspect, P = 0.001). There were no
differences among the 4 groups for 1 mg (26 patients) or 8 mg (18
patients) overnight dexamethasone suppressibility of serum cortisol
levels (data not shown). In addition, there was clear overlap between
all groups for all parameters, including morning serum cortisol, 24-h
UFC, and plasma ACTH levels. Note that 24-h UFC determinations were
either by high performance liquid chromatography with an upper limit of
normal of 50 µg/24 h or by RIA after extraction with an upper limit
of normal of 90 µg/24 h. Not all baseline laboratory results were
available for all patients.
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Performance characteristics of CSS in the 70 patients in whom
surgery was able to identify the ACTH source (Pituitary Proven, n
= 65; Ectopic Proven, n = 5) are shown in Table 2, and the cavernous/peripheral ACTH
ratios are shown in Fig. 4. Using
published cut-offs for IPSS (10), we found that a cavernous/peripheral
ratio of 2.0 or more pre-oCRH stimulation or of 3.0 or more post-oCRH
stimulation (shown as solid lines in Fig. 4) accurately
distinguished Cushing’s disease from the ectopic ACTH syndrome in 93%
of patients before oCRH and in 100% of patients after oCRH. There was
no difference in test performance in patients who had undergone
previous TSS compared to those who had not (data not shown).
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Lateralization
Lateralization ratios were analyzed for their performance in
predicting the intrapituitary location of tumors in those patients in
whom a pituitary adenoma was found and the location documented by the
surgeon (59 of the 65 Pituitary Proven group; the location of the tumor
was not documented in 6 patients). The lateralization ratios are shown
in Fig. 5, and the performance
characteristics of CSS for predicting lateralization are shown in Table 3. To determine whether published
lateralization ratio cut-offs for IPSS provided optimal diagnostic
performance in cavernous sinus sampling, ROC curve analysis of CSS
lateralization ratios was performed. A lateralization ratio cut-off of
1.4 optimized diagnostic performance, correctly predicting the
intrapituitary location of the tumor in 49 of 59 patients (overall
diagnostic accuracy, 83%; see Fig. 5 and Table 3). A positive
lateralization ratio was significantly more accurate in predicting a
lateral tumor (PPV, 85%) than a negative ratio was in predicting a
midline tumor (NPV, 60%). Post-oCRH stimulation CSS was less accurate
than basal CSS, correctly predicting the intrapituitary location of the
tumor in only 40 of 55 patients (overall accuracy, 73%). Results were
similar regardless of whether patients had previously undergone
pituitary surgery (data not shown).
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1.4 predicting a
lateral tumor when the actual location was midline or on the opposite
side of the gland or a ratio <1.4 predicting a midline tumor when the
actual location was lateral) demonstrated that 5 of the 10 cases of
false lateralization could be attributed to a technical factor. In 4
patients there was markedly asymmetric flow favoring the cavernous
sinus opposite the tumor, and in the fifth, the cavernous sinus on the
side of the tumor was hypoplastic, precluding catheterization. MRI
MRI scans detected a tumor in only half of the patients with subsequent proven Cushing’s disease (29 of 58; sensitivity, 55%). In patients in whom a lesion was seen on MRI, it correctly predicted tumor lateralization in 84% of patients compared to surgical findings.
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Discussion |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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The use of oCRH stimulation improved diagnostic accuracy in this series. Similar to published IPSS results, we found a sensitivity of only 93% without oCRH stimulation, which is little better than noninvasive tests. Also similar to IPSS, there was no pre-oCRH ratio cut-off that provided 100% accuracy. Because of this, we recommend that oCRH continue to be used in all patients to optimize the distinction between ectopic and pituitary disease and have established that the published ratio cut-offs of 2.0 or more pre-oCRH stimulation or of 3.0 or more post-oCRH stimulation are also valid for CSS.
Given the high pretest probability of a pituitary adenoma once the diagnosis of ACTH-dependent Cushing’s syndrome has been made, any test used to distinguish pituitary from ectopic disease must have extremely good performance characteristics. Unfortunately, noninvasive laboratory testing does not help further distinguish these patients, and imaging has poor sensitivity. IPSS and now CSS are the only tests to distinguish the two etiologies of ACTH-dependent Cushing’s syndrome with 100% accuracy. However, CSS and IPSS are expensive diagnostic tests, and it has been argued that they should not be used routinely in the evaluation of these patients or that they should be used only in patients who have negative MRI scans. Because of the incidence of pituitary incidentalomas (7), this strategy would result in the misclassification of a significant number of patients and potentially result in inappropriate surgery. Although there are no direct cost-benefit analyses of CSS, Midgette and Aron have performed a cost-effectiveness analysis of IPSS compared to in-hospital evaluation with dexamethasone testing followed by IPSS if the results were equivocal (19). In their analysis, the short term direct costs of initial IPSS testing were higher than those of dexamethasone testing with an option for IPSS. However, IPSS was favorable in terms of long term cost-effectiveness, given its higher accuracy rates, improved identification of patients who need pituitary surgery, and fewer unnecessary surgeries. It follows that CSS, with similar costs and precision as IPSS, would also be cost-effective in the evaluation of these patients, particularly if the superior ability of CSS to predict the intrapituitary location of tumors leads to improved surgical outcomes.
The ability to accurately predict the intrapituitary location of a tumor has direct clinical relevance, because at some institutions if a tumor is not found at TSS, a hypophysectomy is performed. If the intrapituitary location of the tumor can be determined with a high degree of accuracy, a hemihypophysectomy of the predicted side of the tumor can be performed instead, potentially decreasing the rate of postoperative hypopituitarism. We have demonstrated that CSS is highly accurate in predicting the intrapituitary location of tumors, with a positive predictive value of 85% for locating a lateral tumor in all patients and 90% if catheter position is good and there is symmetric venous flow. This is superior to published results for IPSS in all patients where the positive predictive value is less than 70% (10, 11). Similar to IPSS, oCRH stimulation occasionally resulted in false lateralization and was less accurate (overall diagnostic accuracy, 73%) than unstimulated results (10). Notably, CSS was considerably more accurate in locating lateral tumors (PPV, 90% in patients with good catheter position and normal flow) than midline tumors (NPV, only 75%). Fortunately, 90% of tumors have a lateral location, and therefore, this test is likely to provide useful information in the majority of cases. Venous flow asymmetry has been previously evaluated in a small number of patients from one of the larger IPSS series, and asymmetric venous drainage was noted in 39%, which was felt to adversely impact lateralization ability (20). That study and our series emphasize that these technical factors must be noted during the procedure, and lateralization ratios must not be relied upon to guide surgical therapy if there is suboptimal catheter position or significant venous flow asymmetry.
There were 16 patients in our series with a predicted pituitary source of ACTH who were not analyzed because of a lack of evaluable surgery (see Results for details). Five patients did not undergo TSS and therefore could not be evaluated, although 4 had previous TSS with ACTH-producing tumors found; the fifth died before surgery. Eleven patients underwent TSS, with typical gross tumor seen in 7 (1 with an empty sella). Of the 4 in whom no tumor was seen, 1 patient had a prior confirmed diagnosis of Cushing’s disease, and another had an empty sella (suggesting pituitary pathology and making surgical exploration more difficult). The 15 surviving patients have been followed for a mean of 37 months (range, 10–64); in that time, no ectopic tumor has been found. Based on these observations, we believe that these patients most likely have Cushing’s disease; however, we cannot prove this rigorously by our histological and/or cure criteria and therefore excluded these patients from analysis of performance characteristics. As typical TSS failure rates are 10–20% (17), the 11 patients probably represent surgical failures, rather than misclassified patients. The current study was designed to allow comparison of CSS to IPSS, which has been studied most extensively by the NIH (10). In their report on IPSS, they also analyzed only surgically evaluable patients; our current strategy allows us to compare the two techniques most fairly. If, however, we include these 11 Pituitary Suspect patients in the analysis as representing false positive cavernous/peripheral ratios, the sensitivity and NPV of CSS remain 100%, but PPV drops to 86%, and overall diagnostic accuracy falls to 87%.
In our series of patients, there was a significant difference between patients with Cushing’s disease and the ectopic ACTH syndrome with regard to mean morning serum cortisol, 24-h UFC, and peripheral ACTH levels, but there was extensive overlap between the groups for all parameters. This suggests that despite the statistical differences between groups, none of these parameters is useful for distinguishing the two etiologies of Cushing’s syndrome in individual patients. For this reason, we use CSS in all patients for our preoperative evaluation once they have been determined to have ACTH-dependent Cushing’s syndrome.
An accurate diagnosis of ACTH-dependent Cushing’s syndrome is essential before testing with CSS. The basis of CSS is detection of a gradient between the pituitary effluent and the peripheral circulation when ACTH is produced from a pituitary tumor. In contrast, in the ectopic ACTH syndrome, pituitary production of ACTH is suppressed by the high cortisol levels, resulting in no gradient. In a healthy subject or one with hypercortisolism from pseudo-Cushing’s syndrome, there will normally exist a gradient in ACTH levels between the pituitary effluent and the periphery. Indeed, in the two patients who were subsequently believed to have pseudo-Cushing’s syndrome and the normal subject who underwent CSS, cavernous/peripheral gradients of 194, 65, and 49 and lateralization ratios to the right with intercavernous ratios of 9.0, 1.8, and 1.8 were found. These studies would have incorrectly suggested pituitary tumors in these patients if the diagnosis of Cushing’s syndrome had not been clarified. Similar findings have been reported by the NIH with regard to IPSS (21). Likewise, a patient with an ACTH-independent adrenal adenoma might have low, but detectable, ACTH levels, with a central/peripheral gradient, incorrectly suggesting pituitary disease. CSS aids in the differential diagnosis of Cushing’s syndrome only when ACTH-dependent Cushing’s syndrome has been established.
An interesting finding of this study is the accuracy of MRI for detecting tumors. As has been previously reported, MRI had poor sensitivity (55%) in our series for detecting a lesion. Despite its poor sensitivity, if a lesion was seen on MRI, it was likely to represent a tumor and MRI was fairly accurate in predicting lateralization of a tumor (PPV, 84%). This confirms one previous report of high accuracy of MRI for lateralization and low sensitivity for detecting a lesion (22), although a recent study found an accuracy of only 49% (11). One of our patients with the ectopic ACTH syndrome demonstrated a pituitary lesion. This, in addition to the 16% incidence of false lateralization found for pituitary MRI scans, emphasizes the reported prevalence of pituitary incidentaloma, one of the main limitations of relying on MRI scanning for detecting pituitary disease.
Finally, this series demonstrates that CSS can be performed safely. Using standard interventional neuroradiological techniques, it is only slightly more difficult than IPSS. In only 8% of patients could both cavernous sinuses not be cannulated. These were scattered throughout the series and thus probably do not represent our institution’s learning curve. This compares favorably to reported success rates for IPSS (10). Although IPSS has rarely been associated with brain stem ischemia, this was probably related to a particular catheter design (23); the thin, flexible Tracker catheters we use have an excellent safety profile. The main theoretical safety concerns with CSS are cavernous sinus thrombosis and cranial nerve palsies, which were not seen in this series. We do not routinely use anticoagulation, as flow is not usually restricted due to the use of very slow hand contrast injections and the presence of numerous other outflow pathways.
In summary, in this large series of patients with ACTH-dependent Cushing’s syndrome, bilateral simultaneous CSS proved to be safe and efficacious. CSS was able to distinguish patients with Cushing’s disease from patients with the ectopic ACTH syndrome with 100% accuracy. CSS did not eliminate the need for oCRH stimulation, and therefore, it is recommended that oCRH continue to be used. CSS was superior to IPSS for intrapituitary tumor localization, with a PPV of 85% for lateral tumors in all patients and 90% if optimal catheter position was obtained and symmetric flow through the cavernous sinuses was demonstrated. This may assist in the planning of transsphenoidal therapy and avoid the risk of hypopituitarism if hemihypophysectomy needs to be performed. Given this safety and efficacy profile and the previous cost-effectiveness analysis for IPSS (19), we suggest that CSS be performed in all patients with ACTH-dependent Cushing’s syndrome by a qualified angiographer to distinguish pituitary Cushing’s disease from the ectopic ACTH syndrome and to determine intrapituitary tumor location before definitive surgery.
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Acknowledgments |
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Footnotes |
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Received November 9, 1998.
Revised January 15, 1999.
Accepted January 25, 1999.
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References |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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