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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 305-308
Copyright © 1998 by The Endocrine Society

Special Articles

Pitfall of Petrosal Sinus Sampling in a Cushing’s 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 d’Endocrinologie 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 d’Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre F-94275 Kremlin Bicêtre cedex France.


   Introduction
Top
 Introduction
Case Report
 Results
 Discussion
 References
 
THE diagnosis evaluation of ACTH-dependent Cushing’s syndrome (CS) can be a challenge for the physician. Distinguishing between a pituitary adenoma of Cushing’s 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.


   Case Report
Top
 Introduction
 Case Report
Results
 Discussion
 References
 
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 1Go).


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  		Table 1. Hormonal studies consistent with pituitary ACTH-dependent CS, at different times of the patient clinical course

 
Initial hormonal evaluation was consistent with the diagnosis of CD (Table 1Go). 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 2Go). 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 2Go). 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 1Go).


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  		Table 2. IPS and peripheral vein (PV) sampling for ACTH

 
Six months later, hypercortisolism recurred. At that time, neither cortisol nor ACTH responded to CRH (Table 1Go). 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 1Go). 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. 1Go). After removal of the tumor, both plasma CRH and ACTH levels were undetectable (Table 1Go and Fig. 1Go).



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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.

 

   Results
Top
 Introduction
 Case Report
 Results
Discussion
 References
 
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 2Go). 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.

 

   Discussion
Top
 Introduction
 Case Report
 Results
 Discussion
References
 
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.


   Acknowledgments
 
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.


   References
Top
 Introduction
 Case Report
 Results
 Discussion
 References
 

  1. Oldfied EH, Doppman JL, Nieman LK, et al. 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.[Abstract]
  2. Tonon MC, Burlet A, Lauber M, et al. 1989 Immunohistochemical localization and radio immunoassay of corticotropin-releasing factor in the forebrain and the hypophysis of the frog Rana Ridibunda. Neuroendocrinology. 40:109–119.
  3. Wajchember BL, Mendonca BB, Liberman B, et al. 1994 Ectopic adrenocorticotropic hormone syndrome. Endocr Rev. 15:752–787.[CrossRef][Medline]
  4. Schteingart DE, Lloyd RV, Akil H, et al. 1986 Cushing’s syndrome secondary to ectopic corticotropin-releasing hormone-adrenocorticotropin secretion. J Clin Endocrinol Metab. 63:770–775.[Abstract]
  5. Scully RE, Mark EJ, McNeely WF, McNeely BU. 1987 Case records of the Massachusetts General Hospital weekly clinico-pathological exercises. Case 52. N Engl J Med. 317:1648–1658.[Medline]
  6. Zarate A, Kovacs K, Flores M, Moran C, Felix I. 1986 ACTH and CRF-producing bronchial carcinoid associated with Cushing’s syndrome. Clin Endocrinol (Oxf) 24:523–529.
  7. O’Brien T, Young WF, Davila DG, et al. 1992 Cushing’s syndrome associated with ectopic production of corticotrophin-releasing hormone, corticotrophin and vasopressin by a phaechromocytoma. Clin Endocrinol (Oxf). 37:460–467.[Medline]
  8. Orth DN. 1995 Cushing’s syndrome. N Engl J Med. 332:791–802.[Free Full Text]
  9. Malchoff CD, Orth DN, Abboud C, Carney JA, Pairolero PC, Carey RM. 1988 Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor. Am J Med. 84:760–764.[CrossRef][Medline]
  10. Nieman LK, Chrousos GP, Oldfield EH, Avgerinos PC, Cutler GB, Loriaux DL. 1986 The ovine corticotropin-releasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing’s syndrome. Ann Intern Med. 105:862–867.
  11. De Keyzer Y, Lenne F, Auzan C, et al. 1996 The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome. J Clin Invest. 97:1311–1318.[Medline]



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