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Original Article |
Departments of Neuroradiology (V.L., A.V., P.B.), Endocrinology (M.M., I.B., O.C.), Neurosurgery (J.-G.P.), and Cellular Pathology (F.L.-M., N.S.) and Clinical Investigation Center (J.-L.B.), University Hospital of Grenoble, 38043 Grenoble, France
Address all correspondence and requests for reprints to: Dr. Virginie Lefournier, Department of Neuroradiology, CHU Grenoble, BP217, 38043 Grenoble Cedex 9, France. E-mail: virginie.lefournier{at}ujf-grenoble.fr.
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Abstract |
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We retrospectively studied data from 86 patients who underwent BIPSS. Cushing’s disease was predicted in 74 patients, of whom 69 underwent transsphenoidal surgery. Surgical cure was obtained in 65 patients, with identification of a corticotroph microadenoma in 58 cases. In 49 patients the location of the microadenoma predicted by the intersinus ACTH gradient could be compared with the pathologist’s data.
BIPSS accurately predicted the lateralization of the microadenoma in only 57% of these patients. Prediction was improved to 71% when both venograms and catheters were symmetric (35 patients). In this subgroup accuracy was 86% in patients with both catheters in the inferior petrosal sinuses compared with 50% in patients with both catheters in the cavernous sinuses (CS). Two transient sixth nerve palsies occurred during CS catheterization. Our data suggest that BIPSS results are much improved when venous drainage is symmetric. Catheterization of CS did not improve the results and was less safe.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hence, BIPSS is of great help to direct to the neurosurgeon patients with Cushing’s disease who show equivocal results at dynamic testing and/or pituitary magnetic resonance imaging (MRI). However, BIPSS is then less helpful if the neurosurgeon has difficulties in localizing the often very small microadenoma in the pituitaries of these patients. If no microadenoma is apparent at surgical exploration, the neurosurgeon may find it hazardous to rely on BIPSS to choose which side of the pituitary should be removed, which leaves him with the unsatisfactory choice between total hypophysectomy or retreat.
In this study we sought to identify factors that may define a subgroup of patients in whom the accuracy of BIPSS intersinus gradient would be high enough to be reliable. We hypothesized that both the position of the catheters and the symmetry of the venous drainage might influence the value of the intersinus gradient provided by BIPSS. To test this hypothesis we retrospectively studied these two parameters on the venograms obtained in a series of 86 consecutive samplings performed in patients with ACTH-dependant hypercortisolism. Bilateral cavernous sinus sampling (BCSS) has been reported by some researchers to provide a more reliable intersinus gradient (2). In the subgroup of patients who underwent surgery for Cushing’s disease we compared localization of the microadenoma as predicted by either BIPSS or BCSS with actual localization established by the neurosurgeon and the pathologist.
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Subjects and Methods |
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Eighty-six patients (68 women and 18 men; mean age, 43.9 yr; range, 10–81 yr) with ACTH-dependent Cushing’s syndrome underwent either BIPSS or BCSS with oCRH administration in this institution from 1988–2001. ACTH-dependent Cushing’s syndrome was established before BIPSS or BCSS by history, physical examination, and biochemical tests, including in all patients several measurements of 24-h urinary free cortisol, plasma cortisol, and ACTH levels and a 2-mg (0.5 mg every 6 h for 2 d) dexamethasone suppression test. All patients also had at least 1 of the following tests: 8-mg dexamethasone test, 4-mg iv dexamethasone test, and oCRH test. In addition, some patients also had a desmopressin stimulation test. In patients with mild hypercortisolemia, Cushing’s syndrome was confirmed by lack of diurnal variation or by the dexamethasone-suppressed oCRH test (3). All patients underwent a pituitary MRI. BIPSS or BCSS was performed either in patients who showed a normal or inconclusive MRI or in patients who showed an MRI strongly suggestive of pituitary microadenoma but in whom dexamethasone, oCRH, or desmopressin tests did not favor Cushing’s disease. All BIPSS and BCSS were performed by the same team of neuroradiologists (A.V., V.L., and P.B.).
These 86 patients underwent a total of 90 sampling procedures, as 4 of them had 2 inferior petrosal sinus samplings. In 2 patients explored at the beginning of our procedures, BIPSS had to be repeated because the patients proved to be eucortisolic during the first procedure (4). In 2 other patients treated for Cushing’s disease, BIPSS was repeated after recurrence of the disease in the hope of determining the location of the recurrent adenoma. Basal and poststimulation ACTH values were available for all patients, and venograms were available in all but 2 patients. Pituitary MRI scans were available for review in all patients, but were performed in different institutions. MRI scans revealed a tumor in only 19% of the patients; they were negative in 46% and doubtful in 35%. This apparently poor performance of MRI in Cushing’s disease is due in part to a selective bias; most patients are referred to this institution for BIPSS because they have negative or doubtful MRI.
Three patients had undergone transsphenoidal surgery before BIPSS, with either lack of remission or recurrence of symptoms.
Inferior petrosal and cavernous sinus sampling
Bilateral venous catheterization of the inferior petrosal sinuses was performed as previously described (5). Catheterization of both femoral veins was performed, with 7Fr and 6Fr Terumo envoy catheters (Nycomed, Paris, France) inserted percutaneously into, respectively, the right and left femoral veins. In 54 procedures, direct catheterization of the inferior petrosal sinus (IPS) with 4Fr catheters was performed. From 1996, in 36 procedures 6Fr catheters (Nycomed) were placed bilaterally in the jugular bulb, and Tracker-25 infusion catheter (Target Therapeutics-Boston Scientific Corp., Cork, Ireland) were inserted through the guide catheters and advanced using fluoroscopy. When venous anatomical conditions were optimal, the Tracker-25 infusion catheters were positioned in both cavernous sinuses (CS; n = 14). Otherwise when advancing into the CS became difficult (because of venous anatomy mostly plexiform IPS), the catheters remained into the IPS.
Contrast material (5 ml iopamidol 300) was softly injected by hand to obtain digital subtraction venograms of both petrosal and cavernous sinuses in the frontal plane and assess the precise location of the catheter tips. The positions of the catheters were checked fluoroscopically during the procedure. Peripheral blood samples were obtained from the sheath in the right femoral vein. Bilateral central and peripheral blood samples were simultaneously collected. Five sets of basal venous samples were obtained at 3-min intervals, 100 µg synthetic oCRH (UCB Bioproducts, Rockland, ME) was then administrated as an iv bolus, and subsequent poststimulation sets of samples were obtained at 1, 3, 5, and 10 min.
Heparin was not routinely administrated, but 3000 IU heparin as an iv bolus were administrated when the procedure was technically difficult and/or when clotting occurred. The patients studied were continuously monitored with a pulse oximeter, an electrocardiographic monitor, and an automatic blood pressure cuff that measured and recorded both blood pressure and pulse.
To determine whether technical factors in the procedure might have affected the accuracy of lateralization results, digital subtraction retrograde petrosal venograms were analyzed independently by two neuroradiologists without knowledge of BIPSS, BCSS, or surgical results. Flow symmetry was determined by rating the degree of opacification of the inferior petrosal sinus on each side after contrast injection. Three positions of the catheters were defined; the lowest position corresponded to the distal end of the IPS above the basilar plexus, the middle one to the junction between the horizontal and vertical portions of the IPS, and the upper one was within the CS (Fig. 1
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As defined previously (6), pre-oCRH stimulation ratios of 2.0 or more and/or post-oCRH stimulation ratios of 3.0 or more indicated a pituitary source of ACTH. Lateralization ratios of 1.4 or more before oCRH stimulation were used to predict the side of pituitary adenoma; an intersinus gradient less than 1.4 was indicative of a midline lesion. The lateralization ratios were also calculated after oCRH stimulation. The highest central to peripheral ratios before and after oCRH administration were calculated.
Surgical classification
Operative findings served as the gold standard for determining the true location of each patient’s pituitary lesion. Locations were categorized as either lateral right-sided (n = 18), left-sided (n = 16), or midline (n = 15).
Statistical analysis
We used Fisher’s exact test for data analysis (7). The probability value used to identify significance was P < 0.05 with proportions and 95% confidence interval using StatView 5.0 software (SAS Institute, Inc., Cary, NC).
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Results |
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Using a published cut-off for IPSS (6), we found that a central/peripheral ratio of 2.0 or more before oCRH stimulation accurately distinguished Cushing’s disease from the ectopic ACTH syndrome before oCRH in all patients except three (shown as solid lines in Fig. 2). After oCRH those three patients with Cushing’s disease showed a central/peripheral ratio more than 3. However, two patients showed a post-oCRH gradient more than 3, although they did not have corticotroph pituitary microadenoma. The first patient, who was one of the first in our series, had episodic ACTH secretion by a thymic carcinoid tumor and was wrongly explored during a period when she had plasma and urinary cortisol values within the normal range. It has been reported that this situation allows normal corticotroph cells to react to pharmacological stimulation with oCRH, leading to a source of false pituitary localization (8). Since then we systematically checked that all patients were in hypercortisolism just before BIPSS was performed. The second patient had a small bronchial carcinoid tumor apparent on a chest computed tomography scan performed before IPS sampling, and despite the results of BIPSS it was decided to operate upon this bronchial tumor before considering pituitary surgery. The patient was cured by removal of the tumor, which proved to synthesize both oCRH and ACTH (9). A similar case, leading to unnecessary total hypophysectomy, was reported by Young et al. (10). These two patients were thus included in the ectopic ACTH syndrome group.
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IPSS was safely performed in all patients, except in two cases in whom a transient neurological complication (sixth nerve palsy) occurred. One of them has been previously reported (11), and the second one was very similar. Those two complications occurred during catheterization of the CS, and we believe that they might be related to a peripheral sixth nerve injury (see Discussion).
In 90 consecutive procedures, we catheterized both IPS in 82 of 86 patients (96%) The 4 patients in whom IPSS could only be performed on one side had to be excluded from the present study because it was not possible to define their intersinus ACTH gradient.
Of the 86 patients (Fig. 3), 76 were predicted by BIPSS to have a pituitary source of ACTH based on the criteria described above; however, 2 of them were finally diagnosed as an ectopic ACTH syndrome (see above). Thus, 74 patients were advised to have transsphenoidal surgery. Of these 74 patients, 5 did not undergo surgery, 3 received medical treatment, and 2 were followed in other institutions and failed to keep in contact.
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IPSS predicted an ectopic source of ACTH in 12 of the patients, which was localized in 6 cases by removal of an ACTH-staining bronchial carcinoid tumor (n = 5), and 1 thymic carcinoid tumor. In the remaining 6 patients, the ectopic source of ACTH is still occult.
Hence, 58 patients who underwent IPSS could be included in the final sample. However, 9 of those patients were finally excluded: 4 of them because IPSS was only performed on one side; 2 others were excluded because although a corticotroph microadenoma had been removed, we could not identify its precise pituitary location from the surgical and pathological data; 2 were excluded because the venograms could not be retrieved despite extensive research; and the last 1 was excluded because BIPSS was performed after a previous unsuccessful surgery. The final sample then consisted of 49 patients.
Lateralization
Intersinus gradients were analyzed for their performance in predicting the intrapituitary location of tumors in the patients in whom a pituitary adenoma was found and the location was documented surgically (n = 49).
As previously reported (12), a lateralization ratio cut-off of 1.4 considering pre-oCRH values and a simultaneous maximal ratio (Table 1) optimized diagnostic performance, correctly predicting the intrapituitary location of the tumor in only 28 of the 49 patients (57%), without consideration of venous anatomy or symmetry of the catheters.
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) were present in 37 of the 49 patients (75%), whereas asymmetric and/or hypoplastic inferior petrosal sinuses (Miller type III) (13) were present in 12 of the 49 patients (25%; Fig. 4). Symmetric blood flow associated with symmetric position of the catheters was reported in 35 patients, the lateralization ratio of 1.4 then correctly predicted the intrapituitary location of the tumor in 25 patients (71%). This latter result was not significantly different from the former regardless of venous anatomy (57%).
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) and were in the IPS in 21, in either the middle position (n = 14) or the low position (n = 7). The precise posterior-anterior position of the catheter within the CS was not recorded, because lateral views (Fig. 6) were not systematically performed. The lateralization ratio of 1.4 correctly predicted the intrapituitary location of the tumor in, respectively, 7 of 14 patients in the CS (50%) vs. 18 of 21 patients (86%) in the IPS in either the middle position (12 of 14 patients, 86%) or the low position (6 of 7 patients, 86%). The difference between the patients with catheters in the CS and patients with catheters in the IPS (middle or low position) was statistically significant (P < 0.05). Moreover, this latter result (86%) was significantly different from the former regardless of venous anatomy (57%; P < 0.05).
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Post-oCRH stimulation, BIPSS was less accurate than basal BIPSS, as reported in Table 1. Seven of the 74 patients (9%) demonstrated interpetrosal gradient reversal during oCRH stimulation.
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Discussion |
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Regarding lateralization data, our overall estimate was poor, as 57% is well below the degree of certainty required by the neurosurgeon to perform a blind partial hypophysectomy if no microadenoma is found at surgical exploration. However, when we analyzed the influence of the catheter position and the anatomy of the venous drainage, the degree of accuracy rose significantly, up to 86% in the subgroup of patients who had both catheters in either low or middle position in the IPS and symmetric venograms. By contrast, accuracy was only 50% when both catheters had been pushed up to the CS. Finally, lateral gradients measured after oCRH stimulation proved to be less reliable than those before oCRH. When we compare these results with the literature data, we emphasize that the localization of pituitary microadenomas using BIPSS still remains controversial.
Led by Newell-Price et al. (1), a combined analysis of reports published before 1998 revealed that the diagnostic accuracy of simultaneous BIPSS for lateralization of corticotroph microadenomas was 78% (range, 50–100%). Since then, Booth and Bonelli et al. (14, 15) reported 70% accurate localization of the pituitary lesion. For Kaltsas et al. (16) the predictive positive value of the IPS gradient was 74% before oCRH administration and 83% afterward. In an Italian multicenter study performed by Colao et al. (17), BIPSS was surprisingly less reliable in identifying the adenoma site found at surgery than magnetic resonance imaging or computed tomography (65% vs. 75% and 79%, respectively).
Altogether the accuracy of the BIPSS at predicting the microadenoma is approximately 75%. Fewer reports have been published based on CS sampling for which the results, except for BIPSS, show wide differences between the series, from 40–94% as shown below.
Doppman et al. (18) reported correct lateralization results in 40% of patients with Cushing’s disease based on BCSS samples without oCRH administration compared with 60% and 73% based on IPS samples without and with oCRH administration, respectively.
For Mamelak et al. (19), overall venous BCSS and BIPSS correctly lateralized 70% of the tumors. Oliverio et al. (20) reported 60% accurate lateralization with lateral adenoma before oCRH stimulation and 94% after oCRH stimulation. In 40 patients studied by Teramoto et al. (21), the results for lateralization of an ACTH-secreting adenoma were 91% accurate with BCSS, compared with 68% for BIPSS without oCRH stimulation. Recently, Graham et al. (2) reported that BCSS accurately predicted the intrapituitary lateralization of the adenoma in 83% and in 89% with good catheter position and symmetric blood flow.
What is the primary limiting factor to correct lateralization?
Three parameters would interact with the lateralization results: the venous drainage pattern, the sampling site and the oCRH stimulation.
How can the venous drainage pattern influence the lateralization diagnostic accuracy?
With Mamelak and Graham et al. (2, 19), who were the only ones to study the influence of the venous drainage, we can stress that the asymmetric drainage of the cavernous and inferior petrosal sinuses could be the major cause of the incorrect lateralization in both sampling methods. Variations in the venous anatomical features are probably responsible for misleading values. The anatomy of the junction of the inferior petrosal sinus and the internal jugular vein has been studied by Miller et al. (13), and venous anatomy was symmetrical in 65% of subjects (86 of 133). In a control series of 100 patients (22), 75% had large, bilaterally symmetrical IPSs; however, the presence of a unilateral hypoplastic or plexiform inferior petrosal sinus can result in anomalous drainage from the pituitary gland. Such drainage has been reported to result in false negative results regarding the central to periphery ACTH gradient (22), but it very likely also leads to misleading values in the lateral gradient.
Mamelak et al. (19) were the first to analyze the influence of the venous drainage pattern of the IPS. Asymmetric drainage has been demonstrated by CS venography before bilateral venous sampling from the inferior petrosal and cavernous sinuses. When only patients with symmetric venous drainage were considered, CS sampling and IPS sampling were equally reliable methods, correctly lateralizing the tumor in 86% of cases when the drainage was symmetric vs. 44% when it was asymmetric.
Are there advantages to selective samples from the CS?
The influence of the sampling site on the accuracy of the lateralization of the microadenoma is still debated. In our series, as in Doppman’s (18) and Mamelak’s (19), there was no advantage to performing CS sampling rather than IPS sampling in terms of the accuracy of lateralization of the microadenoma. However, we have to consider that in our series we did not perform BCSS and BIPSS on the same patients, which might influence our results.
Other researchers demonstrated high diagnostic accuracy of lateralization o f the microadenoma with BCSS (2, 20, 21). However, in the series reported by Oliverio et al. (20), pituitary MRI images were normal in only 10 of 17 patients. In addition, all patients had high dose dexamethasone suppression tests suggestive of Cushing’s disease. The fact that these researchers had less stringent criteria for BIPSS indication suggests that the differences in the performance of BIPSS lateralization might be affected by selective bias.
For the report by Teramoto et al. (21), it should be noted that the procedure they used was not the same as the procedure that has been advocated and widely used for BIPSS (23). They sampled IPS sequentially after they obtained samples from the CS. In addition, Oldfield and Doppman (24) suggested that there might be a potential selection bias in either the referral or the selection of patients for surgery, as Teramoto et al. (21) stated that BIPSS should be performed in all cases of ACTH-dependent Cushing’s syndrome even if both endocrinological tests and MRI suggest a pituitary lesion.
Another hypothesis for misleading values of BCSS could be related to the posterior-anterior position of the microadenoma within the CS and subsequently to the posterior-anterior position of the microcatheter. For instance, if the microadenoma is located in the posterior portion of the CS, whereas the sampling is performed in the anterior or middle portion of the CS, the ACTH gradients may show false negative results. Teramoto et al. (21) studied the ACTH gradients in unilateral CS in 10 patients. The intracavernous (posterior-anterior) gradients showed a higher concentration of ACTH in the posterior portion of the sinus in all patients. Thus, the discrepancy between the results obtained by several investigators may depend on the sampling sites within the CS.
An additional point remains critical: is CSS as safe as IPSS?
BIPSS is generally safe and well tolerated, although major neurological complications have been reported (8, 15, 16, 17, 18) as well as pulmonary thromboembolisms (1, 19, 20) and a lower extremity deep venous thrombosis (15). We have not encountered those severe complications; however, the two minor neurological complications (transient sixth cranial nerve palsy) we did encounter [one of which has been previously reported (11)] both happened during CS catheterization. Although there have been recent improvements in the catheters and guidewires, which have both become finer and softer, the catheterization may still produce complications, especially when it becomes superselective. In our two patients, the CS was first sought by a soft platinum guidewire, and the microcatheter was then gently advanced to the CS using the guidewire. In both cases, the mechanism was not due to CS thrombosis, because it was transient and remained isolated; moreover, the MRI performed for the second case was normal, and more specifically, angiographic venous sequences showed neither CS nor inferior petrosal sinus thrombosis. Therefore, we believe that these incidents were related to sixth peripheral cranial nerve injury due to either the guidewire or the catheter. These two minor, but bothersome, complications suggest that BCSS might be less safe than BIPSS.
Graham et al. (2) did not encounter either CS thrombosis or cranial nerve palsy, and so stressed that BCSS could be performed safely. However, as we experienced two cranial nerve palsies in our patients, we must point out that BCSS still remains potentially dangerous. We used larger catheters (Tracker 25 Hi Flow catheters) than they did (Tracker 18 Hi Flow catheters); moreover, we took a total of nine blood samples, which implied a long time of sampling (22–25 min; see Subjects and Methods). Both points might have played a role in the two cranial nerve palsies.
Last, is there advantage to oCRH stimulation in the diagnostic accuracy of the lateralization of the microadenoma?
No consensus has been reported from the different series about the advantage of oCRH stimulation in the diagnostic of lateralization. The lateralization results were improved from 74% to 83% after oCRH administration for Kaltsas et al. (16), from 60% to 73% for Doppman et al. (18), and from 60% to 94% for Oliverio et al. (20). In the extensive review by Newell-Price et al. (1), however, oCRH stimulation did not significantly improve the accuracy of the localization, as in our series.
We used microcatheters (Tracker 25 Hi Flow catheters) to cannulate the IPS or the CS, which makes each sampling last more than 30 sec. It should be stressed that because of the proximity of the catheters to the site of secretion, the peak of ACTH secretion after oCRH stimulation is both more sharp and more transient in the IPS than in the peripheral veins. Even though several blood samples are taken, it is quite likely that in the time separating two samplings some peak values could be missed in one sinus, but not in the other (when the adenoma is lateral, ACTH peaks are not supposed to happen at the same time in both sinuses, whereas the samplings are performed at the same time). The missing of an ACTH peak value in one sinus but not in the other would lead to a false lateral gradient during oCRH stimulation. This hypothesis might also explain the occasional reversal of lateralizing gradient that has been reported from the pre- to the post-oCRH values. Miller (25) reported this reversal in 4.5% of the cases, De Herder (26) found it in 3 of 11 patients (25%), and we observed it in 9.5% of our patients.
In conclusion, in our series the overall prediction of lateralization of the pituitary microadenoma remained poor (57%); however, this prediction was significantly better (86%) when the venous drainage was symmetric, and the catheter remained in the IPS. It should be noted that 65 of the 86 patients we initially explored had symmetric drainage. Therefore, we hypothesize that a good prediction of lateralization can be expected in 75% of patients with Cushing’s disease, provided the catheters are placed in the IPS. In our series and several other previous reports, BCSS did not improve the accuracy rate of lateralization. Furthermore, in our hands, BCSS was hampered by two bothersome, although reversible, neurological complications. This suggests that there is no advantage of CS sampling over IPS sampling and that CS catheterization might be less safe than IPS sampling.
Finally, it should be stressed that all studies that analyzed the performance of BIPSS only compared its predictions to the actual localization of a microadenoma that was found and removed by the neurosurgeon. Thus, these studies only stress the superiority of the eye of the neurosurgeon on BIPSS. To better determine whether the intersinus gradient of BIPSS has a real clinical interest, one should analyze its results in the small subgroup of patients in whom the neurosurgeon cannot find an adenoma and decides to proceed to partial hypophysectomy based on the prediction of BIPSS. Such studies have not yet been reported. They might be easier to design now that the performances of BIPSS are better described.
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Acknowledgments |
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We also thank the endocrinologists who referred their patients to our institution for their confidence and contribution: Profs. and Drs. Andreelli, Baudry, Belleville, Benhamou, Bernelle-Mandier, Berthezène, Bertholon-Gregoire, Boizel, Broussolle, Chabrier, Chavot, Chavrier, Cruaud, Darsy, David, Despert, Dhondt, Du Boullay, Ducottet, Echallier, Elkaim, Favre, Fayol, Feige, Fitoussi, Fonti, Geitner, Gernez-Lestradet, Hamon, Honnorat, Jaffiol, Lacheze, Lusset, Mollet, Moulin, Orgiazzi, Paffoy, Pallo, Perrin, Pousset, Prigent, Pugeat, Rioux, Robert, Rodier, Rouge, Rousset, Rueff, Sarrot-Reynauld, Schaegis, Thivollet, Thomas-Soullier, Tourniaire, Tremel, and Waterlot, from the cities of Annecy, Annemasse, Besançon, Bourg en Bresse, Chambéry, Dôle, Evian, Gap, Grenoble, Lyon, Montpellier, Nîmes, Privas, Roanne, St. Etienne, Tours, and Valence.
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Footnotes |
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Received March 11, 2002.
Accepted October 15, 2002.
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References |
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, Patients proven to have pituitary Cushing’s disease; 
, patients with proven ectopic ACTH syndrome. The asterisks indicate two cases in which central/peripheral ACTH ratio wrongly suggested a pituitary adenoma: episodic ACTH secretion by a thymic carcinoid explored during an eucortisolic period, and a rare case of an oCRH- and ACTH-secreting bronchial carcinoid tumor. Shown are the ratio cut-offs that distinguish a pituitary from an ectopic ACTH source before (central/peripheral ratio = 2) and after oCRH stimulation (central/peripheral ratio = 3).
