0013-7227/03/$15.00/0
Printed in U.S.A.
The Journal of Clinical Endocrinology & Metabolism 88(1):196 –203
Copyright © 2003 by The Endocrine Society
doi: 10.1210/jc.2002-020374
Accuracy of Bilateral Inferior Petrosal or Cavernous
Sinuses Sampling in Predicting the Lateralization of
Cushing’s Disease Pituitary Microadenoma: Influence of
Catheter Position and Anatomy of Venous Drainage
VIRGINIE LEFOURNIER, MONIQUE MARTINIE, ASHOK VASDEV, PIERRE BESSOU,
JEAN-GUY PASSAGIA, FRANÇOISE LABAT-MOLEUR, NATHALIE STURM, JEAN-LUC BOSSON,
IVAN BACHELOT, AND OLIVIER CHABRE
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
Bilateral inferior petrosal sinus sampling (BIPSS) is the most
reliable procedure for distinguishing Cushing’s disease from
ectopic ACTH secretion. However, it is less reliable at predicting the lateralization of the pituitary corticotroph microadenoma. We sought to determine whether this could be
improved by taking into account the pattern of venous drainage and the precise location of the catheters.
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. (J Clin Endocrinol Metab 88: 196 –203, 2003)
M
EASUREMENTS OF ACTH after bilateral inferior
petrosal sinus sampling (BIPSS) allow definition of
central to periphery and intersinus ACTH gradients. The
former differentiates Cushing’s disease from ectopic ACTH
syndrome with a diagnostic accuracy close to 100% when
BIPSS is combined with ovine CRH (oCRH) stimulation (reviewed in Ref. 1). By contrast, the intersinus gradient correctly predicts localization of the pituitary adenoma in 78%
of the cases (1). However the differences between the series
are wide, which suggests that the accuracy of ACTH intersinus gradient is affected by some unrecognized factors. In
some series the prediction is accurate in only 50% of the cases,
barely superior to a random prediction, which would be
correct in 33% of the cases, as the choices are among three
different portions of the pituitary (midline, left side, and right
side).
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 neuro-
surgeon 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.
Subjects and Methods
Patients
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 be-
Abbreviations: BCSS, Bilateral cavernous sinus sampling; BIPSS, bilateral inferior petrosal sinus sampling; CS, cavernous sinus; IPS, inferior
petrosal sinus; MRI, magnetic resonance imaging; oCRH, ovine CRH.
196
Lefournier et al. • Lateralization of Cushing’s Pituitary Adenoma
fore 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 ␮g 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
J Clin Endocrinol Metab, January 2003, 88(1):196 –203 197
one to the junction between the horizontal and vertical portions of the
IPS, and the upper one was within the CS (Fig. 1).
Central/peripheral and lateralization gradient ratios
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).
Results
BCSS and BIPSS performance characteristics
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
FIG. 1. Anteroposterior view from retrograde petrosal sinus
venogram demonstrates normal symmetric IPSs. Arrows indicate the
cavernous site of sampling catheters (1), the middle site of sampling
catheters at the junction of the horizontal and vertical segments of
IPS (2), and the low site of sampling catheters in the IPS just above
the basilar plexus (3).
198
J Clin Endocrinol Metab, January 2003, 88(1):196 –203
Lefournier et al. • Lateralization of Cushing’s Pituitary Adenoma
FIG. 2. Central/peripheral ACTH ratios of surgically evaluable patients.
Central/peripheral plasma ACTH ratios before (left) and after (right) oCRH.
E, 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).
ratio more than 3. However, two patients showed a postoCRH 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.
Patient outcomes and surgical classification
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 de-
scribed 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.
Sixty-nine underwent transsphenoidal surgery, and a pituitary source of ACTH was confirmed in 65 of them, either
by demonstration of a pituitary tumor with histological evidence of an ACTH-staining adenoma (n ⫽ 58) or by cure of
the patient’s hypercortisolism by transsphenoidal surgery,
which strongly suggests a pituitary source for the ACTH
even though no tumor was identified by histology (n ⫽ 7).
Four patients underwent surgery, but no lesion was found
histologically, and the patients were not cured.
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).
Lefournier et al. • Lateralization of Cushing’s Pituitary Adenoma
J Clin Endocrinol Metab, January 2003, 88(1):196 –203 199
FIG. 3. Outcomes and surgical classification of patients evaluated with BIPSS. Of the 86 patients referred, 74 were predicted to have a pituitary
tumor (Predicted pituitary) and 69 underwent transsphenoidal surgery (Surgery), with tumor found in 58 (ACTH lesion) or cure after surgery
in 7 (No lesion but cure), both forming the Pituitary proven group. In the other 4 patients, tumor was not found; these patients and the 5 who
did not undergo transsphenoidal surgery were subsequently believed clinically to have pituitary disease and form the Pituitary suspect group.
Twelve patients were predicted to have the ectopic ACTH syndrome (Predicted ectopic). This was proven in 6 patients (Ectopic proven); a tumor
was not found in the remaining 6 patients (Ectopic suspect).
TABLE 1. Accuracy of lateralization ratios from IPS for predicting intrapituitary location of pituitary tumors in patients with proven and
surgically located adenomas (n ⫽ 49)
All patients (n ⫽ 49)
Patients with symmetric venous flow and
symmetric catheter position (n ⫽ 35)
Patients with symmetric venous flow and CS
sampling (n ⫽ 14)
Patients with symmetric venous flow and
IPS sampling (middle position) (n ⫽ 14)
Patients with symmetric venous flow and
IPS sampling (low position) (n ⫽ 7)
Simultaneous maximal pre-CRF
gradient
Simultaneous maximal post-CRF
gradient
n ⫽ 28 (57%) [43%–70%]
n ⫽ 25 (71%) [55%– 85%]
n ⫽ 29 (60%) [45%–72%]
n ⫽ 22 (65%) [46%–77%]
n ⫽ 7 (50%) [27%–73%]
n ⫽ 9 (64%) [39%– 84%]
n ⫽ 12 (86%) [56%–97%]
n ⫽ 10 (71%) [45%– 88%]
n ⫽ 6 (86%)a [49%–97%]
n ⫽ 3 (50%) [16%–75%]
a
a
The lateralization of the tumor was correctly predicted in, respectively 7 of 14 patients in the CS (50%) vs. 18 of 21 patients (86%) in the
IPS, either in the middle position (12 of 14 patients, 86%) or 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 obtained regardless of venous anatomy (57%) (P ⬍ 0.05).
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.
Symmetric inferior petrosal sinuses (Fig. 1) were present
in 37 of the 49 patients (75%), whereas asymmetric and/or
200
J Clin Endocrinol Metab, January 2003, 88(1):196 –203
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
Lefournier et al. • Lateralization of Cushing’s Pituitary Adenoma
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%).
Within the previous group of 35 patients with symmetric
blood flow associated with symmetric position of the catheters, the catheters were in the CS in 14 patients (Fig. 5) 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).
The lateralization ratio was significantly more accurate in
predicting a lateral tumor (76% of the patients with a lateralization ACTH ratio ⬎1.4 had a homolateral tumor) than in
predicting a midline tumor (only 13% of the patients with a
lateralization ACTH ⬍1.4 ratio had a midline tumor).
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.
Discussion
FIG. 4. Anteroposterior view from bilateral retrograde petrosal sinus
venograms demonstrates asymmetric IPSs with a plexiform right IPS
(Miller type III). Montage with the maximal of filling of both IPSs.
Our results first confirm the very high accuracy of BIPSS
in distinguishing between pituitary and ectopic sources of
ACTH secretion (1). Using published cut-off values for pre-
FIG. 5. Anteroposterior view from bilateral retrograde petrosal sinus venograms shows catheter tips (arrows) positioned in the CS through the
IPS catheter. Left, Radiography with no substraction; right, radiography with substraction.
Lefournier et al. • Lateralization of Cushing’s Pituitary Adenoma
FIG. 6. Lateral view demonstrates the position of the catheter tip at
the middle portion of the CS.
and post-oCRH gradients, the prediction of BIPSS was wrong
in only two cases. These two false positives actually represent
two rare situations in which normal corticotroph cells can
secrete ACTH, especially when stimulated by oCRH despite
the presence of a peripheral tumor secreting either ACTH
(intermittently) or CRH. Both situations have been previously described: intermittent ACTH-secreting tumors explored during a normocortisolism period (8) and a CRH-/
ACTH-secreting carcinoid tumor (10). To avoid these rare
pitfalls we recommend that permanence of hypercortisolism
be confirmed just before BIPSS is performed, and that thoracic and abdominal computed tomography scans be systematically performed before BIPSS.
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 cortico-
J Clin Endocrinol Metab, January 2003, 88(1):196 –203 201
troph 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 bilat-
202
J Clin Endocrinol Metab, January 2003, 88(1):196 –203
eral 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 posterioranterior 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 (posterioranterior) 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, 15–18) 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
Lefournier et al. • Lateralization of Cushing’s Pituitary Adenoma
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 lat-
Lefournier et al. • Lateralization of Cushing’s Pituitary Adenoma
eralization 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.
J Clin Endocrinol Metab, January 2003, 88(1):196 –203 203
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Acknowledgments
We are indebted to our colleague Prof. Antoine Tabarin (Bordeaux,
France), who strongly encouraged us to accomplish this analysis of our
data.
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, GernezLestradet, 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, Nı̂mes, Privas, Roanne, St.
Etienne, Tours, and Valence.
Received March 11, 2002. Accepted October 15, 2002.
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@ ujf-grenoble.fr.
16.
17.
18.
19.
20.
21.
22.
References
1. Newell-Price J, Trainer P, Besser M, Grossman A 1998 The diagnosis and
differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states.
Endocr Rev 19:647– 672
2. Graham KE, Samuels MH, Nesbit GM, Cook DM, O’Neill OR, Barnwell SL,
Loriaux DL 1999 Cavernous sinus sampling is highly accurate in distinguishing Cushing’s disease from the ectopic adrenocorticotropin syndrome and in
predicting intrapituitary tumor location. J Clin Endocrinol Metab 84:1602–1610
3. Yanovski J, Cutler GB, Chrousos GP, Nieman LK 1993 Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration:
a new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states.
JAMA 269:2232–2238
4. Bessac L, Bachelot I, Vasdev A, Martinie M, Bonnier L, Chabre O, Passagia
JG, De Rougemont J 1992 Catheterization of the inferior petrosal sinus. Its role
23.
24.
25.
26.
in the diagnosis of Cushing’s syndrome. Experience with 23 explorations. Ann
Endocrinol (Paris) 53:16 –27
Miller DL, Doppman JL 1991 Petrosal sinus sampling: technique and rationale. Radiology 178:37– 47
Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA,
Cutler Jr GB, Loriaux DL 1991 Petrosal sinus sampling with and without
corticotropin-releasing hormone for the differential diagnosis of Cushing’s
syndrome. N Engl J Med 325:897–905
Newcombe RG 1998 Two-sided confidence intervals for the single proportion:
comparison of seven methods. Stat Med 17:857– 872
Yamamoto Y, Davis DH, Nippoldt TB, Young Jr WF, Huston III J, Parisi JE
1995 False-positive inferior petrosal sinus sampling in the diagnosis of Cushing’s disease. Report of two cases. J Neurosurg 83:1087–1091
Chabre O, Mounier C, Martinie M, Vasdev A, Bessou P, Passagia JG, LabatMoleur F, Grino M, Oliver C, Bachelot I 1998 Cushing’s syndrome due to a
lung carcinoid tumor secreting CRH and ACTH: a rare pitfall of inferior
petrosal sinus sampling. Ann Endocrinol (Paris) 59:172
Young J, Deneux C, Grino M, Oliver C, Chanson P, Schaison G 1998 Pitfall
of petrosal sinus sampling in a Cushing’s syndrome secondary to ectopic
adrenocorticotropin-corticotropin releasing hormone (ACTH-CRH) secretion.
J Clin Endocrinol Metab 83:305–308
Lefournier V, Gatta B, Martinie M, Vasdev A, Tabarin A, Bessou P, Berge
J, Bachelot I, Chabre O 1999 One transient neurological complication (sixth
nerve palsy) in 166 consecutive inferior petrosal sinus samplings for the etiological diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 84:3401–
3402
Oldfield EH, Chrousos GP, Schulte HM, Schaaf M, McKeever PE, Krudy
AG, Cutler Jr GB, Loriaux DL, Doppman JL 1985 Preoperative lateralization
of ACTH-secreting pituitary microadenomas by bilateral and simultaneous
inferior petrosal venous sinus sampling. N Engl J Med 312:100 –103
Miller DL, Doppman JL, Chang R 1993 Anatomy of the junction of the inferior
petrosal sinus and the internal jugular vein. Am J Neuroradiol 14:1075–1083
Booth GL, Redelmeier DA, Grosman H, Kovacs K, Smyth HS, Ezzat S 1998
Improved diagnostic accuracy of inferior petrosal sinus sampling over imaging
for localizing pituitary pathology in patients with Cushing’s disease. J Clin
Endocrinol Metab 83:2291–2295
Bonelli FS, Huston III J, Carpenter PC, Erickson D, Young Jr WF, Meyer FB
2000 Adrenocorticotropic hormone-dependent Cushing’s syndrome: sensitivity and specificity of inferior petrosal sinus sampling. Am J Neuroradiol
21:690 – 696
Kaltsas GA, Giannulis MG, Newell-Price JD, Dacie JE, Thakkar C, Afshar
F, Monson JP, Grossman AB, Besser GM, Trainer PJ 1999 A critical analysis
of the value of simultaneous inferior petrosal sinus sampling in Cushing’s
disease and the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol
Metab 84:487– 492
Colao A, Faggiano A, Pivonello R, Giraldi FP, Cavagnini F, Lombardi G 2001
Inferior petrosal sinus sampling in the differential diagnosis of Cushing’s
syndrome: results of an Italian multicenter study. Eur J Endocrinol 144:499 –507
Doppman JL, Nieman LK, Chang R, Yanovski J, Cutler Jr GB, Chrousos GP,
Oldfield EH 1995 Selective venous sampling from the cavernous sinuses is not
a more reliable technique than sampling from the inferior petrosal sinuses in
Cushing’s syndrome. J Clin Endocrinol Metab 80:2485–2489
Mamelak AN, Dowd CF, Tyrrell JB, McDonald JF, Wilson CB 1996 Venous
angiography is needed to interpret inferior petrosal sinus and cavernous sinus
sampling data for lateralizing adrenocorticotropin-secreting adenomas. J Clin
Endocrinol Metab 81:475– 481
Oliverio PJ, Monsein LH, Wand GS, Debrun GM 1996 Bilateral simultaneous
cavernous sinus sampling using corticotropin-releasing hormone in the evaluation of Cushing disease. Am J Neuroradiol 17:1669 –1674
Teramoto A, Yoshida Y, Sanno N, Nemoto S 1998 Cavernous sinus sampling
in patients with adrenocorticotrophic hormone-dependent Cushing’s syndrome with emphasis on inter- and intracavernous adrenocorticotrophic hormone gradients. J Neurosurg 89:762–768
Doppman JL, Chang R, Oldfield EH, Chrousos G, Stratakis CA, Nieman LK
1999 The hypoplastic inferior petrosal sinus: a potential source of falsenegative results in petrosal sampling for Cushing’s disease. J Clin Endocrinol
Metab 84:533–540
Doppman JL, Oldfield E, Krudy AG, Chrousos GP, Schulte HM, Schaaf M,
Loriaux DL 1984 Petrosal sinus sampling for Cushing syndrome: anatomical
and technical considerations. Work in progress. Radiology 150:99 –103
Oldfield EH, Doppman JL 1998 Petrosal versus cavernous sinus sampling.
J Neurosurg 89:890 – 893
Miller DL, Doppman JL, Nieman LK, Cutler Jr GB, Chrousos G, Loriaux DL,
Oldfield EH 1990 Petrosal sinus sampling: discordant lateralization of ACTHsecreting pituitary microadenomas before and after stimulation with corticotropin-releasing hormone. Radiology 176:429 – 431
de Herder WW, Uitterlinden P, Pieterman H, Tanghe HL, Kwekkeboom DJ,
Pols HA, Singh R, van de Berge JH, Lamberts SW 1994 Pituitary tumour
localization in patients with Cushing’s disease by magnetic resonance imaging.
Is there a place for petrosal sinus sampling? Clin Endocrinol (Oxf) 40:87–92