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Original Research |
1 Department of Radiology, Evangelismos General Hospital, 11 Amasias St.,
Athens, Greece 11634.
2 Second Department of Radiology, University of Athens, Athens, Greece.
3 Department of Endocrinology, Evangelismos General Hospital, Athens,
Greece.
Received April 4, 2005;
accepted after revision June 24, 2005.
Address correspondence to S. V. Benakis
(benakis{at}hotmail.com).
Abstract
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MATERIALS AND METHODS: Seventy-eight consecutive patients with CS were included. All patients underwent biochemical investigation and pituitary MRI. Consequently, patients were routinely referred for BIPSS; 25 received stimulation with corticotropin-releasing hormone (CRH) and 53 with CRH and desmopressin. The diagnosis of CD was established on the basis of complementary biochemical, imaging, and BIPSS criteria. The diagnostic performances of BIPSS and MRI were calculated for patients with final diagnosis.
RESULTS: A final diagnosis was available for 54 patients (46 CD confirmed, five ectopic confirmed, three adrenals). No (known) patient was misclassified based on our suggested diagnostic criteria. MRI rendered 25 false-negatives and two false-positives (incidentalomas). Successful BIPSS yielded two false-negatives and three false-positives (adrenals). The calculated accuracy for detecting a pituitary source of ACTH was 50% and 88% for MRI and successful BIPSS, respectively.
CONCLUSION: MRI is of only limited diagnostic performance, while BIPSS is the most accurate way to establish the diagnosis of CD. The routine use of a multimodality diagnostic approach including BIPSS, MRI, and biochemical tests is suggested to avoid the risk of mismanagement for patients with CS.
Keywords: Cushing's disease • Cushing's syndrome • interventional radiology • MRI • neuroimaging • venography
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Large pituitary adenomas (> 10 mm) are rare and usually present with mild manifestations of CS [3]. Pituitary corticotrophic microadenomas (< 10 mm) are responsible for ACTH-dependent CS in most patients, but their identification and precise localization are not always feasible because of their small size. In the remaining patients, hypersecretion of ACTH originates from small, often occult, ectopic sites. Thus, differentiating between these two conditions is a veritable challenge.
Imaging procedures have limited value in the differential diagnosis of CS for three reasons: the low sensitivity of MRI [4-6] and despite apparently better results of dynamic MRI, higher sensitivity is followed by lower specificity [7]; the significant incidence of pituitary asymptomatic microadenomas in the general population [8]; and the difficulty in locating small ectopic sites, which often remain radiologically unidentified for a long time [9].
Bilateral inferior petrosal sinuses sampling (BIPSS), however, despite being invasive and elaborate, is established as a highly accurate diagnostic procedure in distinguishing pituitary from ectopic sources of ACTH [9-11] and has changed the management options of CS dramatically. The existence of a significant ACTH gradient between venous samples from the inferior petrosal sinuses (IPS) and the periphery (P) is considered diagnostic of pituitary-dependent CS, whereas its absence suggests ectopic ACTH secretion [12, 13]. Although basal ACTH gradients are sufficient in many occasions to establish pituitary hypersecretion [12], the sensitivity of BIPSS is greatly improved by the assessment of ACTH gradients obtained after the administration of corticotropin-releasing hormone (CRH) [5, 14]. Moreover, as reported in our previous study in a smaller group of patients [15] and by Kaltsas et al. [5] in a limited number of patients, the sensitivity of the procedure is improved further when using a combination of CRH and desmopressin for the stimulation of ACTH.
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Biochemical Investigation
The source of ACTH secretion was initially searched by routine noninvasive
biochemical investigations including a high-dose dexamethasone test (2 mg
dexamethasone orally every 6 hours for 2 days) and a CRH test (human CRH
[hCRH], 100 µg IV bolus).
Imaging
All patients were examined with pituitary MRI performed in different
centers. Scans were obtained with the same protocol
[7] in all patients using a
1.0-T or 1.5-T scanner. T1-weighted spin-echo sequences in the coronal and
sagittal planes with a slice thickness of 3 mm and a cranial scan in a
T2-weighted spin-echo sequence in the coronal plane were obtained. Then a
T1-weighted turbo spin-echo dynamic acquisition in the coronal plane was
started simultaneously with the bolus injection of gadolinium-DTPA (0.1
mmol/kg body weight) with a 3-mm slice thickness and was followed by a
contrast-enhanced T1-weighted spin-echo sequence in the coronal and sagittal
planes with a 3-mm slice thickness.
Imaging interpretation was performed independently by two experienced radiologists with knowledge of all associated clinical and biochemical information but blinded to surgical and histopathologic results. In case of disagreement, scans were reviewed and evaluated by consensus between the two radiologists. Radiographic interpretations of the pituitary MRI were recorded and classified, according to the literature, as definitely positive (evidence of a small hypointense region with respect to normal parenchyma on unenhanced T1-weighted spin-echo or a focal hypoenhancing lesion on the contrast-enhanced scan, or both); questionable (indirect signs such as a bulge on the surface of a gland, deviation of the pituitary stalk, or an asymmetric sellar floor but no direct evidence of pituitary tumor); or negative (no visible tumor). When findings appeared negative or the interpretation was questionable, MRI was classified as negative for statistical analysis.
At the time of presentation, total-body CT and whole-body planar somatostatin release inhibiting factor (SRIF) receptor scintigraphy using 111Inpentetreotide were performed in all patients to exclude the presence of an ectopic ACTH-producing tumor. In addition, further follow-up examinations were performed every 6 months in patients with predicted ectopic ACTH-dependent CS until an ACTH-secreting source was identified.
Catheterization Protocol
All patients with CS were routinely referred for BIPSS. Bilateral IPS
catheter insertion was performed according to the technique described
previously [12]. Two 5-French
hydrophilic-coated vertebral catheters were introduced into the right and left
femoral veins using the Seldinger technique. The catheters were manipulated
into both IPS. A small amount of nonionic contrast medium was injected to
verify the position of the catheters (Fig.
1). Correct catheter placement with the tip at the junction of the
vertical and horizontal segment of the IPS was confirmed. Blood samples (6 mL)
were collected simultaneously from both catheters
(Fig. 2) and a peripheral vein
over a 2-minute period, before (basal levels) and at 3-5, 8-10, and 13-15
minutes after (peak levels) bolus administration of either 100 µg of hCRH
in the first 26 procedures (25 patients) or 100 µg of hCRH plus 10 µg
desmopressin in the remaining 55 procedures (53 patients). The procedure was
defined as successful when satisfactory catheterization of both IPS was
achieved. Plasma ACTH was measured using a highly specific immunoradiometric
assay. Intra- and interassay coefficients of variation were 4% and 8%,
respectively. The highest ratio of ACTH values in IPS samples, to the level
measured at the same time from the peripheral vein samples, was calculated
both before and after stimulation and used as an indicator for the diagnosis
of Cushing's disease (CD).
Diagnostic Criteria
The diagnosis of CD was based on the following: a decrease of more than 50%
of serum cortisol after the high-dose dexamethasone test or an increment of
cortisol more than 20%, or both; ACTH more than 50% over the baseline value
after the CRH test (biochemical criterion); a suspicious or definitely
positive finding suggesting a pituitary adenoma seen on MRI (imaging
criterion); and an IPS/P gradient of more than 2 (IPS/P gradient 3
2) at baseline or poststimulation during BIPSS
[4,
5,
9,
14] (BIPSS criterion), or
both.
Patients with BIPSS-positive findings for CD in established ACTH-dependent CS, BIPSS-negative findings for CD, positive MRI, and discordant or positive biochemical results, or BIPSS-negative findings, MRI equivocal findings, and positive biochemical results were referred for transsphenoidal surgery.
Diagnostic Confirmation
Pathologic and clinical criteria for the establishment of the source of
ACTH production were similar to those suggested by Oldfield et al.
[12]. A pituitary source of
ACTH was established by histologic confirmation of an ACTH-secreting pituitary
adenoma (pathologic criterion) or cure or significant remission of the
hypercortisolism after pituitary microsurgery even if no tumor was found
(clinical criterion). This last criterion was based on the experience that
those tumors are typically semisolid, soft, or milky in consistency and are
often not recovered for pathologic analysis
[13]. The diagnosis of ectopic
ACTH-dependent CS was made by identification of an extrapituitary
ACTH-secreting tumor or its metastasis during initial workup or at follow-up
examinations or both. An adrenal disease (ACTH-independent CS) was confirmed
by histologic evidence of a primary adrenal abnormality (an adrenal functional
tumor or unilateral adrenal hyperplasia).
Statistical Analysis
The main statistical analysis was limited to patients with a confirmed
diagnosis. The clinically relevant parameters of BIPSS and MRI, respectively,
characterized by sensitivity, specificity, accuracy, positive predictive
value, negative predictive value, false-positive ratio, and false-negative
ratio, were calculated by comparing the findings of each diagnostic procedure
with surgical findings supplemented by histologic details and clinical
outcomes.
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Complications
The sampling procedure was safely performed in all patients. Apart from
facial flushing and transient ear discomfort reported during selective
catheterization of the IPS, no other side effects were observed.
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The remaining six patients, despite a negative BIPSS indicative of an ectopic syndrome, satisfied the diagnostic criteria, as discussed earlier, for pituitary surgical exploration. Surgery resulted in apparent cure or histologic examinations revealed the presence of a pituitary ACTH-secreting microadenoma, or both. Therefore, the previously mentioned patients were finally included in the pituitary confirmed group (Fig. 3).
BIPSS in the Differential Diagnosis of Cushing's Syndrome
In patients with proven CD, BIPSS was performed with CRH alone in 20
patients and CRH plus desmopressin in 26 patients. The mean basal IPS/P ACTH
gradients were similar in the two groups and significantly higher compared
with patients with proven ectopic ACTH-dependent CS. However, the mean peak
IPS/P ACTH gradients were higher in the CRH plus desmopressin group compared
with those obtained in the CRH group.
Six patients (four in the CRH and two in the CRH plus desmopressin group) showed a peak IPS/P ACTH gradient of less than 2 after stimulation, classifying the pituitary as an ectopic source of ACTH (six false-negatives). However, in four of them (three in the CRH group and one in the CRH plus desmopressin group), the procedure was not technically successful (high jugular vein sampling, unilateral inferior petrosal sinus sampling, or both), making it impossible to recognize whether the sampling was really negative in predicting a pituitary source or negative because of technical failure. On this basis, taking into account only patients who underwent successful bilateral catheterization, false-negative findings occurred in only two of them (one receiving stimulation with CRH alone and one with CRH plus desmopressin).
All five patients with subsequently proven ectopic ACTH-dependent CS showed an IPS/P gradient of less than 2 both before and after stimulation and were correctly diagnosed by BIPSS (true-negatives).
It is noteworthy that the three patients with adrenal disease studied after a combined stimulation with CRH plus desmopressin had an IPS/P gradient of more that 2, similar to patients with pituitary disease (peak gradients of 3.4, 14, and 61.8, respectively; false-positives). Two of them had nonsuppressed ACTH levels before the procedure (basal gradients of 3.8 and 2.1, respectively). One of the three patients had both a pituitary and a left adrenal lesion found by imaging before BIPSS. Basal ACTH gradients were very low (1.0) but detectable, and post combined stimulation with CRH and desmopressin increased IPS/P ACTH gradients (3.4) were observed, incorrectly suggesting CD. However, the very low basal ACTH levels in the presence of an adrenal lesion suggested an adrenal rather than a pituitary source of the hypercortisolism. The patient underwent left adrenalectomy, and total cure was observed. Although the BIPSS results for the three patients with adrenal disease were equivocally positive (ACTH independency), they have been included in our statistical calculations.
Consequently, sensitivity of BIPSS for the diagnosis of CD was 86.9%, whereas specificity was 62.5%, causing an accuracy of 83.3%. Negative and positive predictive values of 45.4% and 93% were calculated, and the false-negative and false-positive ratios were 13.1% and 37.5%, respectively. However, the sensitivity, negative predictive value, and false-negative ratio of the procedure for the diagnosis of CD were markedly improved to 94.4%, 71.4%, and 5.6%, respectively, when taking into consideration only patients with successful bilateral catheterization. Moreover, a trend of higher sensitivity (95.2%) and negative predictive value (83.3%) and a lower false-negative ratio (4%) was observed in the patient group with successful bilateral catheterization receiving stimulation with CRH plus desmopressin. Table 1 shows the diagnostic performance characteristics of BIPSS for the diagnosis of CD in patients with a final diagnosis.
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MRI in the Differential Diagnosis of Cushing's Syndrome
MRI detected a discrete lesion in only 28 of 78 patients
(Fig. 4). Transsphenoidal
surgery was performed in 24 of the 28 patients. The presence of an
ACTH-secreting pituitary adenoma was confirmed pathologically in 21 of these
24 patients. Three of the 24 patients underwent transsphenoidal surgery and
gross tumor was found, but histologic results were inconclusive. They were not
cured by surgery, and no ectopic tumor has been located at a mean follow-up of
44 months. We assumed that these patients suffered from CD but it could not be
proven; they therefore were excluded from statistical analysis. Four of 28
patients did not undergo surgery: Two MRI-positive patients did not meet the
criteria for transsphenoidal surgery. Both of them were subsequently found to
have nonpituitary lesions; one had a medullary carcinoma of the thyroid, and
one had unilateral adrenal hyperplasia. It is very likely that in the patients
just cited, positive MRI findings were related to the presence of pituitary
incidentalomas or corresponded to technical artifacts (false-positives); the
remaining two patients with positive findings were excluded from statistical
calculations: One patient refused surgery, and one was lost to follow-up.
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In four of 50 MRI-negative patients, an ectopic source of ACTH was found (four bronchial carcinoids; true-negatives). Two of 50 MRI-negative patients had a final consensus diagnosis of adrenal disease (true-negatives). Another seven MRI-negative patients are clinically considered ectopic but this has not been proven; they were excluded from our statistical analysis.
The sensitivity of MRI for localizing a pituitary source of ACTH was calculated as 45.6%; specificity as 75%; and accuracy as 50%. Negative and positive predictive values of 19% and 91.3%, respectively, were calculated. The false-negative ratio was 54.3% and the false-positive ratio, 25%. Table 1 illustrates the diagnostic performance figures of MRI in detecting CD in patients with a final diagnosis.
In total, CD was predicted in 63 patients by one or more diagnostic procedures, based on the previously described criteria, with a final consensus diagnosis in 46 of them. Forty of these patients were correctly diagnosed by BIPSS and 21 by pituitary MRI. A final consensus diagnosis was obtained in 54 patients (Fig. 5). Overall, BIPSS showed a significantly higher sensitivity of 86.9% but a lower specificity of 62.5% than MRI (sensitivity, 45.6%; specificity, 75%) in detecting a pituitary source of ACTH secretion. Moreover, an increased sensitivity of BIPSS was observed in the patient group with successful bilateral catheterization (n = 44) (sensitivity, 94.4%), and a slight further increase in sensitivity was observed in patients with successful bilateral catheterization receiving stimulation with CRH plus desmopressin (n = 29) (sensitivity, 95.2%) (Table 1).
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MRI is commonly used to investigate CD and remains the obvious technique to identify pituitary microadenomas noninvasively. However, the MR tomographic identification of pituitary ACTH-secreting tumors has proved to be particularly problematic. Table 2 offers a summary of performance characteristics as documented in the literature [5-7]. ACTH-secreting microadenomas are frequently not visible on MRI in patients with CD. This is in part because of their small size, or it could be related to the fact that those lesions have signal and enhancing characteristics similar to the normal pituitary gland. Another notable limitation of MR identification of CD is the high incidence of false-positives. These false-positive images are believed to correspond to blurring artifacts or pituitary incidentalomas [7]. In fact, approximately 10% of the healthy adult population has pituitary abnormalities on MRI that are compatible with the diagnosis of asymptomatic microadenomas [16].
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The proportion of false-negative MRI results in our study population stood at 54.3%, and the sensitivity and negative predictive values were calculated as 45.6% and 19%, respectively. This means that in more than half of patients in whom final consensus diagnosis returned evidence of a pituitary source of ACTH, MRI failed to show the presence of tumor. It is interesting to note that in 13 of 25 patients with false-negative MRI findings, both surgical exploration and pathology failed to recognize the presence of an ACTH-secreting adenoma. The final diagnosis of CD was unequivocal for these patients because total cure of the hypercortisolism after surgery was obtained. Similar to our results, total cure of the hypercortisolism after hypophysectomy but no histologic evidence of tumor was reported by other investigators [6, 17, 18]. According to these observations, a significant percentage of pituitary ACTH lesions are histologically silent. This means that these lesions hypothetically could be missed radiologically despite continuous technical advancements that enhance resolution and increase the sensitivity.
We also experienced two false-positive results (one patient with adrenal disease and one with ectopic ACTH-dependent CS) on MRI (specificity, 75%; positive predictive value, 91.3%; false-positive ratio, 25%). These false-positives apparently corresponded to asymptomatic microadenomas or technical artifacts. This particular aspect of pituitary imaging raises uncertainty regarding whether a pituitary lesion detected on MRI, if not confirmed by other complementary diagnostic procedures, could be coincidental and at times misleading, resulting in unnecessary hypophysectomies and permanent patient disability. Hence, MR tomographic capability for correctly diagnosing CD appears to be severely restricted (accuracy, 50%).
We recognize that our study presents several limitations. First, our institution is a referral center for endocrine disorders; thus, our collective is skewed toward undiagnosed cases of CS (patients with inconclusive imaging or biochemical findings), and a selection bias inevitably introduced in our patient population could cause our results to underestimate the accuracy of MRI. Another limiting characteristic is the retrospective nature of our study with consequent introduction of methodologic variables such as different magnets and scan parameters, despite the use of the same imaging protocol in all patients.
A number of studies have evaluated the role of BIPSS in the differential diagnosis of CS. Many experts consider BIPSS after CRH stimulation to be the most powerful means of differentiating pituitary from ectopic sources of ACTH. Oldfield et al. [12] published their experience with this technique in a large patient population, reporting a sensitivity and specificity of 100%. In more recent series, however, both false-negative and false-positive results have been reported. Table 3 summarizes the diagnostic performance figures of BIPSS in detecting a pituitary source of ACTH as reported in previous studies [1, 5, 12, 18-22]. Our results first confirm the very good performance of BIPSS in distinguishing pituitary from ectopic sources of ACTH (Table 2). In our series, there were six false-negatives (sensitivity, 86.9%; negative predictive value, 45.4%; false-negative ratio, 13.1%). However, in four sampling procedures, the catheterization was not technically successful, which could theoretically be responsible for the false-negatives. Excluding patients with technically unsuccessful catheterization, sensitivity rose to 94.4%, but we still failed to identify two patients with CD. In previous studies, others have also reported false-negatives [1, 5, 19-22]. Swearingen et al. [22] stated that false-negatives after BIPSS procedures are significantly more common than previously appreciated and a negative BIPSS does not rule out a pituitary source.
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We initially assumed that false-negatives could possibly be avoided by using CRH plus desmopressin instead of CRH alone for the stimulation of ACTH. This hypothesis was sustained in our previous study in a smaller group of patients [15] showing amplified response of pituitary-derived ACTH secretion and improved sensitivity obtained with the combined stimulation with CRH plus desmopressin in comparison with CRH stimulation alone. However, although a combined stimulation was applied systematically in 55 consecutive procedures, one false-negative has still been isolated (sensitivity, 95.2%). Whether this finding was related to intrinsic characteristics of tumor secretion, technical factors, or error in sampling manipulation is unclear, and we believe that further research in this direction is necessary.
Another interesting and unexpected finding in our study was the presence of increased gradients after combined stimulation observed in the three patients with adrenal disease (classified as false-positives). Isolated examples illustrating similar BIPSS findings were published by Swearingen et al. [22], who excluded these cases from statistical calculations because of their ACTH independency. Two of the three patients had unsuppressed ACTH levels before the procedure. Presumably, adrenal tumors with intermittent cortisol production could incompletely suppress endogenous ACTH production and allow an IPS/P gradient to persist [23]. In the third patient, basal ACTH gradients were very low but were detectable, and increased gradients were observed after stimulation. We therefore assume that BIPSS aids the differential diagnosis of CS only when ACTH-dependent CS is established (specificity 100% in ACTH-dependent CS). It is worthy of mention that this apparent diagnostic limitation of BIPSS does not seem to affect patients with adrenal disease in terms of classification and management because our referring clinicians seem to have little trouble in differentiating pituitary from adrenal disease using noninvasive biochemical tests.
A statistical disadvantage of this study is the small number of patients with histologically confirmed ectopic ACTH-dependent CS (n = 5). As a result, reported specificities and positive predictive values should be interpreted with caution and need to be reevaluated with more data in the future.
In our series, 24 patients (30.7%) were excluded from statistical analysis for lack of final diagnosis. Those patients currently being managed as if they have presumed pituitary or presumed ectopic tumors represent an important subgroup in clinical practice. This is similar to the approach used in previous studies [6, 18, 22]. Seven of 24 undiagnosed patients are managed on the basis of a negative BIPSS procedure, as if they had an occult ectopic syndrome. It is important to remember that occult ectopic ACTH-dependent CS is usually caused by carcinoids, especially of bronchial origin, and the situation is made more complicated by the fact that these tumors can be undetectable for years [7, 16]. Seventeen of the 24 patients just mentioned were excluded from our analysis of performance characteristics because of a lack of evaluative surgery. Eleven of them refused surgery or were lost to follow-up and therefore a final consensus diagnosis was not available. The remainder underwent pituitary surgery, but pathology failed to confirm the diagnosis of a corticotrophic microadenoma, and they were not cured. We believe these six patients represent cases of surgical failure rather than misclassified patients (three of them had prior pituitary surgery that probably led to anatomic alterations, making surgical exploration more complicated). Graham et al. [6] reported similar failure rates for transsphenoidal surgery.
In theory, routine diagnostic tests should be safe, largely available, highly effective, and easy to perform at low cost. BIPSS is the reference diagnostic standard for the identification of ACTH-secreting tumors, but it is technically demanding and relatively expensive. Midgette and Aron [24] published a cost-effectiveness analysis of BIPSS compared with in-hospital evaluation with noninvasive testing followed by BIPSS when results were inconclusive. They stated that BIPSS was favorable in terms of long-term cost-effectiveness given its high accuracy rates in identifying patients who needed pituitary surgery. In our series, BIPSS procedure was performed safely in all patients. Complications from the procedure reported in the literature are rare but significant. Major neurologic complications and pulmonary thromboembolisms have been reported [9, 25, 26]. Thus, it has been argued that BIPSS should not be used as a screening diagnostic test in patients with CS but should be performed selectively in patients with negative or inconclusive MRI findings [17, 27]. Ilias et al. [28] proposed the use of jugular vein sampling as an easier and less expensive alternative to perform in centers with limited BIPSS experience, reserving the use of confirmatory BIPSS for patients with negative jugular vein sampling.
We believe that BIPSS remains the single best diagnostic technique and routine BIPSS evaluation of patients with CS at initial diagnostic approach should be considered as suggested previously [6, 21] but BIPSS is a technically challenging procedure; therefore, the only true limitation to its wide routine clinical use is the unequivocal need for a skilled radiology team to catheterize the IPS correctly and avoid major complications [25]. If BIPSS studies were performed routinely before transsphenoidal surgery, even in patients with definitely positive MRI, theoretically it could serve as a guide to avoid unnecessary pituitary surgery in a significant number of patients with nonfunctional microadenomas. It is this particular aspect of pituitary MRI (inability to distinguish between functional and nonfunctional microadenomas) that led to the recommendation of performing BIPSS before transsphenoidal surgery as a first-line diagnostic test in all patients with CS as the major result of our study.
It is generally agreed that pituitary MRI makes only a limited diagnostic contribution to the differential diagnosis of ACTH-dependent CS [21, 29, 30]. However, it is noteworthy that in our series, six patients with subsequently proven CD were diagnosed incorrectly by BIPSS. These patients underwent pituitary surgery with consequent cure of the hypercortisolism based on our suggested diagnostic criteria, which included biochemical evidence of CD and positive or suggestive MRI. These observations suggest that negative BIPSS results, in the presence of contradictory data from other complementary techniques, should be viewed with concern and eventually lead to the consideration of pituitary surgical exploration if no other source of ACTH can be shown [22].
In conclusion, CS presents a complex problem of differential diagnosis and management that is best undertaken by dedicated multidisciplinary teams. We believe that, at least in specialist referral centers, past concerns regarding the invasiveness, technical difficulty, and relatively high cost of BIPSS should be effectively overcome. BIPSS together with MRI should be used as a first-line routine diagnostic approach, and patients should be considered on a case-by-case basis, taking into account both radiologic and biochemical findings to minimize the risk of patient misclassification and mismanagement.
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