Pitfall of Petrosal Sinus Sampling in a Cushings Syndrome Secondary to Ectopic Adrenocorticotropin-Corticotropin Releasing Hormone (ACTH-CRH) Secretion
Jacques Young,
Catherine Deneux,
Michel Grino,
Charles Oliver,
Philippe Chanson and
Gilbert Schaison
Service dEndocrinologie et des Maladies de la Reproduction,
Hôpital Bicêtre (J.Y., C.D., P.C., G.S.) F-94275 Kremlin
Bicêtre and INSERM U 297, (M.G., C.O.) F-13326 Marseille,
France
Address all correspondence and request for reprints to: Gilbert Schaison, M.D., Service dEndocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre F-94275 Kremlin Bicêtre cedex France.
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Introduction
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THE diagnosis evaluation of ACTH-dependent
Cushings syndrome (CS) can be a challenge for the physician.
Distinguishing between a pituitary adenoma of Cushings disease (CD)
and an ectopic ACTH-producing tumor is very often difficult. Patients
with either tumor may respond similarly to routine tests such as
high-dose dexamethasone suppression or metyrapone test. In addition,
the small size of most ACTH-secreting pituitary microadenomas and many
ectopic ACTH-producing tumors may cause false negative imaging results.
Thus, over the past ten years, inferior petrosal sinus (IPS) sampling
has been proposed as the gold standard for the differential diagnosis
between pituitary and nonpituitary ACTH-dependent CS. With the
adjunctive use of corticotropin releasing hormone (CRH), the diagnostic
accuracy of this test reaches almost 100% (1). The present report
demonstrates that IPS sampling with CRH stimulation has not the same
reliability in case of concomitant ectopic ACTH-CRH secretion.
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Case Report
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A 60-yr-old man was referred for evaluation of CS. He
presented with a 12-month history of 12 kg weight gain, muscular
weakness, and hypertension. Physical examination revealed truncal
obesity, redness of the face, moon facies, buffalo hump, and
supraclavicular fossa fullness, but no purple striae. He had severe
proximal muscular atrophy, several small ecchymotic areas over the
extremities, and skin atrophy, but no melanodermia. Blood pressure was
190/110 mm Hg. Routine laboratory studies performed on admission showed
hyperglycemia (glucose concentration: 11 mmol/L), hypokalemia
(potassium: 2.7 mmol/L), and metabolic alcalosis (bicarbonate: 31
mmol/L). CS was confirmed on elevated free urinary cortisol, lack of
plasma cortisol circadian rhythm, and resistance to the 2-day low-dose
(2 mg) dexamethasone test (Table 1
).
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Table 1. Hormonal studies consistent with pituitary
ACTH-dependent CS, at different times of the patient clinical course
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Initial hormonal evaluation was consistent with the diagnosis of
CD (Table 1
). Adrenal function was suppressed after the 2-day high-dose
(8 mg) dexamethasone test, and plasma ACTH and cortisol increased after
administration of synthetic ovine CRH (100 µg iv). Pituitary magnetic
resonance imaging (MRI) was normal, and a computed tomography scan of
the abdomen revealed two enlarged adrenals and a 2-cm retropancreatic
mass. 111In-pentetreotide scintigraphy (IPS) did not show
any abdominal spot. Simultaneous peripheral vein and IPS sampling
showed, before and after CRH stimulation, an increased right
IPS-peripheral ACTH gradient (Table 2
).
In addition, before considering pituitary surgery, catheterization of
thoracic, azygos, hepatic veins, and inferior and superior veina cava
for ACTH measurements was performed three weeks later. No ectopic
source of ACTH secretion was identified. During this procedure, a
second IPS sampling clearly confirmed the petrosal-to-peripheral ACTH
gradient (Table 2
). These results were consistent with the presence of
a pituitary corticotroph microadenoma, possibly in the right side.
Transsphenoidal exploration of the pituitary gland was carried out but
failed to uncover a pituitary adenoma. Total hypophysectomy was
performed, and the whole pituitary gland was thoroughly examined.
Immunocytochemistry showed a normal density of corticotropic cells,
with no any distinct adenoma or atypical corticotropic cell
hyperplasia. Following pituitary surgery, panhypopituitarism with a
dramatic drop of plasma ACTH and cortisol levels occurred (Table 1
).
Six months later, hypercortisolism recurred. At that time, neither
cortisol nor ACTH responded to CRH (Table 1
). This led us to reconsider
the source of ACTH. Surgical removal of the retropancreatic tumor
provoked a fall in ACTH and cortisol, which then became undetectable
(Table 1
). During surgery, samples for ACTH and CRH measurements (2)
were obtained from the tumoral vein. An increased tumoral-to-peripheral
vein ACTH and CRH gradient was observed (Fig. 1
). After removal of the tumor, both
plasma CRH and ACTH levels were undetectable (Table 1
and Fig. 1
).

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Figure 1. A, CRH levels in the tumoral vein and a
peripheral vein (PV) before and after removal of the neuroendocrine
tumor. (ND: not detectable). B, Plasma ACTH levels in the tumoral vein
and a peripheral vein before and after tumor resection.
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Results
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Pathological examination showed a 3-cm retropancreatic
tumor. Histologically, the aspect was typical of a carcinoid tumor.
Pleomorphism was moderate, and mitotic figures were only occasionally
seen. Multiple foci of vascular invasion and the presence of three
lymph node metastases confirmed the malignant nature of the tumoral
tissue. Immunohistological examination was positive with
neuron-specific enolase and chromogranin A antibodies.
Immunohistochemical staining for ACTH and CRH (2) were positive (Fig 2
). In addition, high immunoreactive CRH
levels were found in the tumor (65 ± 9 fmol/g).

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Figure 2. Immunohistochemical staining of serial
sections of the neuroendocrine tumor with anti-ACTH (A) and anti-CRH
(B) antibodies.
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Discussion
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The neuroendocrine tumor of this patient produced both ACTH
and CRH. The unequivocal tumor production of CRH was demonstrated by
the tumoral-to-peripheral vein gradient, the direct radioimmunoassay of
the peptide in the tumor and the immunohistochemical study showing CRH
staining in the tumor cells. Before hypophysectomy, ACTH production in
this patient originated from two separate sources: 1) the pituitary
gland as demonstrated by two IPS samplings and the dramatic decrease of
ACTH after hypophysectomy; 2) the tumor itself, as indicated by the
tumoral-to-peripheral ACTH gradient, the positive immunostaining for
this peptide in the tumor, the persistent measurable plasma ACTH levels
after hypophysectomy, and the undetectable ACTH levels after tumor
resection.
Well documented concomitant ectopic CRH and ACTH secretion are
extremely rare (3, 4, 5, 6, 7). This situation is known to affect the results of
dynamic testing of the pituitary-adrenal axis and to complicate the
differential diagnosis of CS (8, 9, 10). Indeed, this patient had
responses to high-dose dexamethasone suppression and CRH test similar
to the results observed in patients with CD. In cases of isolated
ectopic ACTH-secreting tumors, the pituitary ACTH secretion is
suppressed by the high circulating levels of cortisol. In contrast, in
the ectopic CRH syndrome, the pituitary production of ACTH is
maintained and even stimulated. Similar results have been previously
reported (5, 7). False positive IPS-peripheral ACTH ratios of greater
than 2 have been detected in patients with ectopic production of CRH.
In the present study, total hypophysectomy was performed, offering the
opportunity to compare the results of dynamic testing in the absence or
presence of the pituitary corticotropic cells. Before hypophysectomy,
plasma F and ACTH levels increased in response to CRH test. After
removal of the adenohypophysis, the CRH test was negative. These
results indicate that the response initially induced by CRH occurred
directly at the pituitary level and was not mediated by its own
receptor at the level of the tumor, as previously reported (11).
Simultaneous peripheral vein and bilateral IPS sampling with CRH
stimulation is the best technique for tracking the ACTH source of CS.
However, its diagnostic accuracy and reliability are questionable in
case of concomitant secretion of ACTH and CRH by a neuroendocrine
tumor.
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Acknowledgments
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We gratefully acknowledge Dr M. Kujas and J. Trouillas for
performing the immunohistochemical studies of the pituitary gland.
Received August 5, 1997.
Accepted October 10, 1997.
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