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Original Studies |
Diagnostic Radiology Department, Warren Grant Magnuson Clinical Center (J.L.D., R.C.); Developmental Endocrinology Branch, National Institute of Child Health and Human Development (G.C., C.A.S., L.K.N.); and Division of Intramural Research, National Institute of Neurological Disorders and Stroke (E.H.O.), National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints: John L. Doppman, Diagnostic Radiology Department, Building 10, Room 1C660, 10 Center Drive MSC 1182, Bethesda, MD 20892-1182. E-mail: jdoppman{at}nih.gov
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Introduction |
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On review, the clue to the false-negative result of petrosal sampling in each patient was the presence of a hypoplastic or plexiform IPS (Miller type III) (3) on the side of the microadenoma. The hypoplastic or plexiform sinus permitted filling of the ipsilateral cavernous sinus at the time of retrograde venography and therefore, led to the presumption that the catheter was positioned appropriately to sample blood from the ipsilateral cavernous sinus. It is our hypothesis, however, that the presence of the catheter obstructed the hypoplastic or plexiform petrosal sinus and altered the venous drainage pattern, thereby causing the false-negative sampling results. The presence of a hypoplastic or plexiform IPS may be a clue to the potential unreliability of the results of petrosal sinus sampling, even with CRH stimulation, and should lead either to the selective catheterization of the cavernous sinus (often difficult in the presence of a hypoplastic or plexiform IPS) or to an attempt to sample the alternate drainage route demonstrated by the contralateral retrograde venogram.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Patient 1 did not suppress on high
dose (8 mg/day twice) dexamethasone. Patient 3 had cyclic
ACTH-dependent hypercortisolemia and a positive ACTH but negative
cortisol response to CRH. She was always sampled when her cortisol
levels were elevated. Sampling patients with cyclic Cushing’s syndrome
because of an ectopic ACTH-producing tumor during a normocortisolemic
phase can lead to a false-positive diagnosis of Cushing’s disease when
normal pituitary corticotrophs are not suppressed but should not lead
to a false-negative result.
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All four patients had negative (n = 2) or equivocal (n = 2) MRI scans of the pituitary gland before petrosal sinus sampling. T1-weighted (TR 400, TE 7–9 msec) MRI scans were performed with a 1.5 Tesla scanner (Signa, General Electric, Milwaukee, WI). Contiguous 3-mm-thick sections of the pituitary gland were obtained in the coronal and sagittal planes before and after the iv administration of 0.1 mmol/kg of gadopentetate meglumine (Berlex, Inc., Wayne, NJ).
Following the nondiagnostic petrosal sinus sampling, the first three patients underwent serial CT and MRI examinations of the neck, chest, and abdomen searching for a source of ectopic ACTH production. These examinations were repeated approximately every 6 months for up to 36 months until the correct diagnosis (Cushing’s disease) was established. The following invasive procedures were performed in searching for the alleged ectopic ACTH-producing tumor: thoracotomy (n = 1) for enlarging cryptococal granuloma, percutaneous portal vein sampling (n = 2), transventricular pulmonary vein sampling (n = 1), ERCP and endoscopic ultrasound of the pancreas (n = 1), CRH injection into right and left pulmonary arteries with sampling of the aortic root for ACTH (n = 1). Patient 2 underwent bilateral adrenalectomy when medical suppression failed. Pituitary MRI was also performed at regular intervals because the source of ACTH remained occult. It became positive in three of the four patients, lending support to the diagnosis of Cushing’s disease.
Our most recent patient (no. 4) underwent timely transsphenoidal surgery because sampling of the internal jugular vein on the side of the plexiform IPS was positive for elevated ACTH levels and because, by this time, the hypoplastic IPS was recognized as a potential cause of false-negative sampling results.
All four patients became normo (n = 1) or hypocortisolemic (n = 3) after transsphenoidal resection of a pituitary microadenoma that stained positively for ACTH.
One author (J.L.D.) reviewed the retrograde inferior petrosal sinograms of 100 consecutive patients with ACTH-dependent Cushing’s syndrome, excluding the patients reported here. There were 67 females with an average age of 37 yr (range 10–73 yr) and 33 males with an average age of 33 yr (range 5–65 yr). Each petrosal sinus was classified as larger (L) or equal/smaller (S) than the contrast-filled lumen of the catheter visualized on the same digitally subtracted coronal images. The sinus and the catheter lumen were measured on subtracted digital radiographs using a vernier caliper with digital readout (Mitotoyo Corp., Japan). The frequency of unilateral or bilateral hypoplastic or plexiform IPSs was recorded.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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presents laboratory, imaging, sampling, and surgical
findings in the four patients with Cushing’s disease and
false-negative results of petrosal sampling. All patients had
measurable plasma ACTH levels and responded to CRH (10); there were
mixed responses to high-dose dexamethasone suppression (11) tests (3 of
4 indicated Cushing’s disease) and metyrapone (12) stimulation tests
(2 of 3 indicated Cushing’s disease). Two patients (nos. 1 and 3) had
negative pituitary MRI scans and petrosal sampling studies at outside
institutions before referral to the National Institutes of Health
(NIH).
The IPS was narrowed or plexiform on the left in three patients
and on the right in one patient. Figure 1
shows normal IPSs (Fig. 1A) and an atrophic right IPS (Fig. 1B) in
patient 1. In all patients the abnormal sinus was ipsilateral to the
ultimately discovered ACTH-secreting microadenoma. In all instances, it
was possible to position the sampling catheter in the abnormal IPS and
opacify the ipsilateral cavernous sinus at retrograde venography.
However, retrograde venography from the contralateral IPS failed to
fill the jugular vein on the side of the hypoplastic petrosal sinus,
but opacified multiple collateral veins connecting to the
prevertebral venous plexus. In Patient 2, the external jugular vein
appeared to be the drainage route, and sampling from this vessel at the
time of the third petrosal sampling procedure provided diagnostic ACTH
gradients. No retrograde venogram from the normal IPS was performed
without the catheter in the contralateral atrophic IPS, so the role of
the catheter in diverting flow by obstructing the atrophic sinus could
not be evaluated. In patient 4, samples from the internal jugular vein
were positive in the presence of false-negative ipsilateral petrosal
samples (Fig. 2) but in patient 3, both
inferior petrosal and internal jugular samples were negative.
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In the control series of 100 patients, 75% had large, bilaterally
symmetrical IPSs. In this group, the presence of sampling catheters in
the IPSs did not perturb drainage patterns (Fig. 1A). Eighteen percent
had asymmetrical IPSs: the small sinus was on the left in 11 patients
and on the right in 7 patients. In 7%, the petrosal sinuses were
bilaterally small, i.e. equal or smaller in diameter than
the 4 French sampling catheter and at risk of obturation with the
catheter in position. In spite of the 25% incidence of unilateral or
bilateral atrophic petrosal sinuses, none of these patients had
false-negative sampling results. Figure 3
illustrates a patient with an atrophic left IPS not affecting the
reliability of the sampling.
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Case Reports
Patient 2. This 28-yr-old male physicist presented in August
1989 with severe Cushing’s syndrome suggestive of ectopic ACTH
production. He had weight gain and fatigue, severe proximal muscle
weakness, difficult-to-control hypertension, diabetes with retinopathy,
hypokalemia, and severe osteoporosis. MRI of the pituitary gland was
normal. Bilateral petrosal sinus sampling with CRH stimulation showed a
baseline right petrosal gradient (539 pg/mL ACTH) but no gradients
after CRH. His laboratory tests indicated Cushing’s disease, because
urinary free cortisol (UFC) excretion suppressed on dexamethasone (8
mg), and plasma ACTH and cortisol levels increased after CRH
administration. Because of the single positive value on IPS sampling,
petrosal sinus sampling with CRH administration was performed a second
time during his initial admission and failed to reveal ACTH gradients
at any time point (Fig. 4A). Retrograde
venograms at the time of both petrosal sampling studies revealed an
atrophic left IPS but the left cavernous sinus filled from a left
petrosal sinus injection (Fig. 4B). Retrograde right inferior petrosal
venograms performed with the left petrosal sinus catheter in place
showed drainage of the left cavernous sinus into the left external
jugular vein (Fig. 4C), but at that time the significance of this
finding was not appreciated.
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During the ensuing 3 yr the patient had eight admissions to NIH,
searching for the presumed ectopic source of ACTH production. In
December 1990, the patient underwent right thoracotomy for a rapidly
enlarging right lower lobe nodular mass, suspected to be an oat cell
carcinoma. A 2 x 3-cm atypical cryptococcoma was removed. In
December 1991, the patient underwent endoscopic retrograde
cholangiopancreatography and endoscopic ultrasound to evaluate a
suspicious lesion of the pancreatic head on CT scan. These studies were
normal. Petrosal sinus sampling was repeated in September 1991.
Conventional petrosal sinus sampling revealed no gradients, but there
was a large elevation of ACTH in samples from the left external jugular
vein, which was recognized as the drainage route of the left cavernous
sinus (Fig. 4D). However, because of the bilateral adrenalectomy and
replacement therapy, we could not, with certainty, distinguish a left
ACTH-secreting microadenoma from the normally asymmetric sampling
results in physiologically normal subjects (15). A repeat MRI of the
pituitary on March 1992 demonstrated a microadenoma on the left, which
was removed completely at transsphenoidal surgery and stained
positively for ACTH.
Comment. This patient illustrates the problem of interpreting the results of petrosal sinus sampling following bilateral adrenalectomy. In Cushing’s syndrome, the high levels of plasma cortisol suppress completely ACTH production by the normal pituitary corticotrophs but only incompletely suppress ACTH production by a corticotroph adenoma. Following bilateral adrenalectomy, the normal pituitary corticotrophs are no longer suppressed and elevated levels of ACTH in IPS samples compared with the simultaneous peripheral values are routinely obtained, particularly after CRH stimulation, even in the presence of an ectopic ACTH-producing tumor. Elevated levels of ACTH from an ectopic source do not suppress ACTH production by the normal corticotrophs of the pituitary gland once cortisol levels are normalized by bilateral adrenalectomy or medical suppression. The problem of identifying an overlooked pituitary source of ACTH is even more complex following bilateral adrenalectomy.
Patient 3. This 34-yr-old woman had insulin-dependent diabetes
of 14 yr duration and a history of thyroiditis. She developed mild
Cushingoid signs and symptoms, but following a normal MRI of the
pituitary gland and nondiagnostic petrosal sinus sampling results at an
outside institution, she was given the diagnosis of pseudo-Cushing’s
syndrome. On admission to NIH (May 1996), her UFC levels were elevated.
Plasma cortisol were suppressed after dexamethasone 8 mg at 2300
h. The response to stimulation with CRH was mixed, with no change in
plasma cortisol values but an increase in plasma ACTH. The initial MRI
at our institution was equivocal on the left, but two subsequent
studies were negative. IPS sampling failed to show ACTH gradients in
either petrosal sinus before and after CRH stimulation. There was,
however, a systemic response to CRH, suggesting ectopic ACTH production
by a CRH responsive tumor. The left IPS was atrophic but even in
retrospect an alternate venous drainage pathway was not seen (Fig. 5A). Jugular vein sampling with CRH
stimulation was also negative. The patient was given a diagnosis of
ectopic ACTH syndrome and a search initiated for the responsible tumor.
MRI of the chest and abdomen were negative as well as an octreotide
scan. Because of a suspicious lesion in the pancreas on CT scan, the
patient underwent portal venous sampling for ACTH; no gradients were
found. The patient’s hypercortisolism was suppressed with ketoconazole
and she was discharged with a diagnosis of ectopic ACTH syndrome.
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, B and C).
Eighteen months after initial investigation a fifth MRI scan with an
augmented dose of gadopentetate meglumine revealed a microadenoma in
the left half of the pituitary gland. A 6-mm microadenoma that stained
positively for ACTH was removed by transsphenoidal surgery (December,
1997) and all symptoms of Cushing’s disease have remitted. Comment. Direct sampling from the cavernous sinus should compensate for the problems arising from an atrophic or plexiform IPS. In this patient, the atrophic left IPS accommodated the Tracker catheter but was probably obturated by it. Tracker catheters introduced into the cavernous sinus generally sample from the posterior portion of the cavernous sinus. The cavernous sinus is not an empty blood-filled cavern, but is divided into innumerable locules by multiple septae. Even with lateral fluoroscopy, it is sometimes difficult and frequently painful to advance the catheter into the anterior sinus. But sampling from the posterior cavernous sinus with the patient supine should be reliable. We hypothesize that the Tracker catheter in the atrophic left IPS obstructed flow and led to alternate drainage of the left cavernous sinus into ophthalmic and superior petrosal sinus routes. Diversion of the left cavernous sinus flow into the right cavernous sinus would have been detected by the Tracker catheter simultaneously sampling the right cavernous sinus. We have no explanation for why sampling the cavernous sinuses with CRH stimulation failed to reveal elevated levels of ACTH in this patient on two separate occasions.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An extremely rare cause of false-positive IPS sampling would be a patient with ectopic production of CRH. These patients would demonstrate elevated levels of ACTH in the IPSs caused by pituitary corticotroph hyperplasia secondary to CRH production from an ectopic tumor. Young et al. (18) recently described such an unusual occurrence and a similar case was reported in the Case Records of the New England Journal of Medicine (19).
False-negative results of IPS sampling occur in 5% of patients with Cushing’s disease before CRH stimulation, but in our experience (1), false-negative results are extremely rare after stimulation with CRH. Lopez et al. (20) reported one post-CRH false-negative inferior petrosal sampling in 24 patients with surgically proven Cushing’s disease. McNally et al. (21) also reported an example of a false-negative inferior petrosal sampling in the presence of Cushing’s disease. Because neither of these authors illustrated the venographic anatomy of the IPSs, one can only speculate whether an atrophic sinus contributed to these results.
Teramoto et al. (7) proposed the routine performance of cavernous sinus rather than IPS sampling in the differential diagnosis of Cushing’s disease from ectopic ACTH syndrome. They introduce Tracker catheters sequentially into the right and left cavernous sinuses and obtain nonsimultaneous samples without CRH stimulation. Mamelak et al. (8), also recommend routine catheterization of cavernous sinuses, but their purpose is to perform retrograde venograms to better interpret the reliability of lateralization. Our experience (22) has been that in most cases selective sampling of the cavernous sinus is not necessary and adds expense and invasiveness to the procedure. When a plexiform or atrophic IPS is encountered, however, anomalous drainage patterns may be present, particularly with the catheter obturating the petrosal sinus on the same side as the microadenoma. In these circumstances an attempt should be made to obtain samples from the cavernous sinus, recognizing that the abnormal IPS may prevent selective placement of the catheter. This was true in patient 4 with bilateral plexiform cavernous sinuses.
In patient 3, the cavernous sinuses were sampled and an ACTH gradient was not detected. Catheter placement in the posterior compartment of the cavernous sinus was documented by lateral fluoroscopy. It is possible that the presence of the catheter in an atrophic sinus obstructs the IPS, and therefore perturbs the drainage patterns of the cavernous sinus so that alternate drainage routes such as the superior ophthalmic vein or superior petrosal sinus are used.
The frequency of uni- or bilateral atrophic IPSs (25%) is much higher than the occurrence of false-negative results of petrosal sinus sampling in patients with Cushing’s disease. Even when the atrophic sinus occurs on the side of the pituitary microadenoma, a true positive petrosal sinus sampling is probably the rule. However, when the contralateral retrograde venogram shows no filling of the atrophic petrosal sinus and collateral flow into other venous systems, the possibility of a false-negative sampling result must be entertained. A positive MRI study of the pituitary on the side of the atrophic sinus would increase suspicion and should lead to performance of selective cavernous sinus sampling. However, the 10% incidence of pituitary incidentalomas (23) cautions against relying on positive pituitary MRI scans as unequivocally establishing the diagnosis of Cushing’s disease.
Endocrinologists accept bilateral IPS sampling with CRH stimulation as the most reliable test for differentiating between an ACTH-secreting pituitary microadenoma and an ectopic ACTH-producing tumor. A sensitivity of 99% has been reported both by our group (1) and others (2). So much confidence is placed in this test that a negative result may delay transsphenoidal surgery, lead to medical suppression of hypercortisolemia with its potential complications, and to serial imaging studies searching for ectopic ACTH-producing tumors. When an ectopic ACTH-producing tumor is not discovered, and medical suppression fails, the patient may undergo bilateral adrenalectomy.
In our four patients, classic suppressive (high-dose dexamethasone suppression) and stimulative (metyrapone and CRH) tests were generally diagnostic of Cushing’s disease. In two patients, an equivocal adenoma was imaged in the pituitary gland, but transsphenoidal surgery was not performed because of the negative results of petrosal sinus sampling and the suspicion that we were dealing with an incidentaloma of the pituitary gland (23).
All of our patients had a hypoplastic or plexiform IPS on the same side as the ultimately resected pituitary microadenoma. In each case, the sampling catheter was positioned so that a retrograde injection of contrast material filled the ipsilateral cavernous sinus. However, retrograde venograms from the contralateral side failed to demonstrate drainage of the atrophic sinus into the internal jugular vein, suggesting that the sampling catheter in the atrophic sinus obstructed this sinus and led to altered drainage patterns in this low-pressure system. When a hypoplastic IPS is encountered, the angiographer must keep in mind that the ability to fill the ipsilateral cavernous sinus via retrograde injection does not assure a successful sampling of the ipsilateral cavernous sinus effluent.
Miller et al. (3) described the anatomy of the IPS and its junction with the internal jugular vein. In the majority of cases, the sinuses are symmetrical bilaterally (type 1 and 2). In type 4 anatomy, the petrosal sinus has no connection with the ipsilateral internal jugular vein. When this anatomy is present, one recognizes that sampling is unachievable and an alternate drainage route is sought. It is the type 3 anatomy with a unilateral hypoplastic or plexiform IPS that may mislead the angiographer. Because the cavernous sinus can be opacified by a retrograde injection into such a hypoplastic sinus, there is a presumption that cavernous sinus blood is being sampled. When the ACTH-secreting pituitary microadenoma is ipsilateral to an hypoplastic IPS, an incorrect diagnosis of ectopic ACTH syndrome may result.
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Acknowledgments |
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Received August 20, 1998.
Revised October 14, 1998.
Accepted October 19, 1998.
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