(Radiology. 2000;214:195-198.)
© RSNA, 2000
Case 18: Adrenocorticotropic Hormone-dependent Cushing Syndrome1
Peter L. Choyke, MD and
John L. Doppman, MD
1 From the Department of Diagnostic Radiology, Imaging Sciences Program, Clinical Center, National Institutes of Health, Bldg 10, Rm 1C660, 10 Center Dr, MSC 1182, Bethesda, MD 20892-1182. Received August 28, 1998; revision requested September 25; revision received October 26; accepted April 6, 1999. Address reprint requests to P.L.C. (e-mail: pchoyke@nih.gov).
Index terms: Adrenal gland, abnormalities, 86.541, 86.317 • Adrenal gland, CT, 86.1211 • Adrenal gland, neoplasms, 86.317 • Cushing syndrome, 86.541 • Diagnosis Please • Hormones • Pituitary, MR, 145.1214 • Pituitary, neoplasms, 145.1269, 145.317
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HISTORY
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A 45-year-old woman presented with a history of central obesity and blood pressure of 160/105 mm Hg. A computed tomographic (CT) scan of the abdomen (Fig 1) and a magnetic resonance (MR) image of the pituitary gland (Fig 2) were obtained.
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Figure 1a. Transverse contrast material-enhanced CT scans of the abdomen demonstrate (a) a poorly enhancing mass (curved arrow) arising from the right adrenal gland. The remaining adrenal tissue (straight arrows) is thickened instead of atrophic and is also shown in b, an image obtained slightly caudad to a.
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Figure 1b. Transverse contrast material-enhanced CT scans of the abdomen demonstrate (a) a poorly enhancing mass (curved arrow) arising from the right adrenal gland. The remaining adrenal tissue (straight arrows) is thickened instead of atrophic and is also shown in b, an image obtained slightly caudad to a.
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IMAGING FINDINGS
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The patient presented with signs and symptoms of Cushing syndrome. The adrenal mass on the right side (Fig 1) and the normal appearance of the contrast-enhanced MR image of the pituitary gland (Fig 2) would at first suggest an adrenal adenoma that is overproducing cortisol rather than one that is adrenocorticotropic hormone (ACTH) dependent. However, in spite of the right adrenal mass, the limbs of the ipsilateral and contralateral adrenal glands are hyperplastic rather than atrophic as would be expected with an autonomous Cushing adenoma. Thus, the cause of Cushing syndrome in this case is most likely a nonvisualized pituitary microadenoma with secondary adrenal macronodular hyperplasia.
Further work-up included petrosal venous sampling (Fig 3) that demonstrated a petrosal-to-peripheral ACTH gradient greater than 3, as well as an intersinus gradient across the pituitary gland, which was diagnostic of a right-sided ACTH-producing pituitary adenoma. Thus, the patient has pituitary Cushing syndrome, or more appropriately, ACTH-dependent Cushing syndrome. An ACTH-positive pituitary adenoma was resected, and the patient currently has normal cortisol levels.
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Figure 3. Venogram of the petrosal sinus veins (arrows) obtained during sampling of ACTH. The ACTH levels in the right and left petrosal veins are 86 pg/mL (18.6 pmol/L) and 4 pg/mL (0.8 pmol/L), respectively, and the peripheral ACTH level is 5 pg/mL (1.1 pmol/L). This indicates adenoma of the right side of the pituitary gland (p).
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DISCUSSION
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This case illustrates the importance of observing the thickness of the unaffected limbs of the adrenal gland in the setting of Cushing syndrome and an adrenal nodule. Autonomous cortisol-producing adenomas of the adrenal gland suppress ACTH levels and result in atrophy of the remaining adrenal tissue. This is illustrated in Figure 4, which demonstrates, in another case, a hyperfunctional Cushing adenoma with atrophic adrenal limbs. In the setting of Cushing syndrome and a unilateral adrenal mass, it is tempting to ascribe the symptoms to an autonomous adrenal adenoma and perform adrenalectomy, but this would not be curative in this case.
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Figure 4. Transverse contrast-enhanced CT scan of the adrenal glands in a patient with Cushing syndrome that is not ACTH dependent demonstrates a low-attenuation dominant mass (open arrows) and atrophic limbs (solid arrows) of the remaining adrenal glands.
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When a pituitary adenoma produces excess ACTH, it leads to hyperplasia of the adrenal glands. This occasionally will result in macronodular hyperplasia (ie, one or more functional nodules that are nonetheless not autonomous) (1). Micronodular hyperplasia also occurs but is not seen at imaging. Incidental but nonhyperfunctional adenomas, which are found in 1%–2% of the general population, may simply coexist with Cushing syndrome (2). Alternatively, the mass could represent a pheochromocytoma or aldosteronoma, but in the present case neither entity is associated with central obesity (3). Moreover, pheochromocytomas are usually of lower attenuation than the lesion shown, and aldosteronomas are usually smaller.
It is important to note that atrophy of the normal limbs of the adrenal glands does not always occur with a hyperfunctional adrenal adenoma, but normal or thickened adrenal limbs and an adrenal nodule, in the clinical setting of Cushing syndrome, should raise concern about ACTH-dependent Cushing syndrome (1). If the remainder of the glands are hyperplastic, the possibility of an ACTH-dependent macronodular hyperplasia with a unilaterally dominant nodule should be considered (1,4).
Whenever a patient has Cushing syndrome, it is worthwhile to consider the possible causes. The most common cause (68% of cases) is an ACTH-secreting pituitary adenoma, which is usually suspected on the basis of elevated peripheral ACTH levels (5). If a definite pituitary adenoma is not identified on routine gadolinium-enhanced MR images of the pituitary gland, petrosal venous sampling should be performed. Petrosal venous sampling allows the surgeon to identify which half of the pituitary gland contains an adenoma. The surgeon then "bread loafs" (slices the pituitary methodically from one side to the other) that half of the pituitary gland until the adenoma is found and removed.
Doppman et al (6) recently investigated the role of jugular venous sampling to replace the more technically demanding petrosal venous approach. Petrosal venous sampling with stimulation of corticotropic releasing hormone is nearly 100% accurate in distinguishing pituitary from ectopic ACTH production (7). Intraoperative ultrasonography of the pituitary gland can aid the neurosurgeon in identifying the pituitary microadenoma (8). The sensitivity of this technique in patients with negative MR images is 84%, with a specificity of 33% (9).
The next most common cause (18% of cases) of Cushing syndrome is a hyperfunctional adrenal adenoma or carcinoma (5). These lesions are characteristically of lower attenuation on CT images obtained before the administration of contrast material, which reflects the relatively high concentration of steroidal lipids. At chemical-shift MR imaging, out-of-phase images will demonstrate a loss of signal intensity compared with that on in-phase images, which again reflects the high lipid content. In many institutions, such lesions can now be approached laparoscopically, which dramatically decreases the morbidity associated with adrenal surgery (10). The nonadenomatous adrenal tissue should be atrophic, which reflects suppressed ACTH levels.
Other, less common causes of Cushing syndrome include ectopic ACTH production, primary pigmented nodular adrenal disease, and massive macronodular hyperplasia. In ectopic ACTH production, which occurs in approximately 12% of patients, Cushing syndrome is caused by an ACTH-producing tumor outside of the pituitary gland (5). These are usually carcinoid tumors, such as bronchial and thymic carcinoid tumors, arising from the foregut (11,12). Pheochromocytomas, islet cell tumors, and oat cell carcinomas also can secrete ACTH, but they do so less commonly. Diagnosis can be difficult because these tumors are often small yet produce sufficient quantities of ACTH to produce clinical manifestations. Thin-section CT of the lung is warranted in this setting to detect these lesions. Occasionally, when the primary tumor cannot be delineated, bilateral adrenalectomies are performed.
Massive macronodular hyperplasia (13) and primary pigmented nodular adrenal disease (14) are two rare causes of Cushing syndrome that is not ACTH dependent, and they account for less than 1% of cases (5). In the former, the adrenal glands are multinodular and markedly enlarged, whereas in the latter the functional nodules are usually small, darkly pigmented at inspection, and may not be seen at CT. Both require bilateral adrenalectomy with long-term gluco- and mineralocorticoid replacement therapy.
Another cause of hypercortisolism is surreptitious or factitious use of steroids. This is seen in Munchausen syndrome.
A radiologist attentive to these imaging nuances can prevent unnecessary adrenalectomy and direct appropriate management of Cushing syndrome in a patient with a unilateral adrenal mass.
Our congratulations to the 28 individuals who submitted the most likely diagnosis (adrenocorticotropic hormone–dependent Cushing syndrome) for Diagnosis Please, Case 18. Credit was given if there was mention of ACTH-dependent Cushing syndrome. The names and locations of the individuals, as submitted, are as follows:
- Gholamali Afshang, MD, Tinley Park, Ill
- Lionel Arrivé, MD, Paris, France
- William W. Atherton, DC, Chesterfield, Mo
- Kenneth Baliga, Rockford, Ill
- Giuseppe Brancatelli, MD, Palermo, Italy
- Peter Corr, Durban, South Africa
- Danny Eisenberg, MD, Las Vegas, Nev
- Seyed A. Emamian, MD, PhD, Washington, DC
- Akira Fujikawa, Tokyo, Japan
- Athanassios D. Gouliamos, MD, Athens, Greece
- Ferris M. Hall, MD, Boston, Mass
- Mitchell A. Klein, MD, Milwaukee, Wis
- Gildo Matta, MD, Cagliari, Italy
- Sergio J. Moguillansky, MD, Rio Negro, Argentina
- Eduardo Mondello, MD, Buenos Aires, Argentina
- Vung Duy Nguyen, San Antonio, Tex
- Enrique Remartinez Escobar, Melilla, Spain
- Luiz Antonio Rossi Pierre-Jean Sauvage, Macon, France
- Matt Shapiro, MD, Lowell, Mass
- Paolo Siotto, MD, Cagliari, Italy
- J. Takasugi, Mercer Island, Wash
- Mehmet Teksam, MD, Minneapolis, Minn
- Douglas L. Teich, MD, Brookline, Mass
- Norman B. Thomson, III, MD, Savannah, Ga
- Carlos E. Triana Rodriguez, Santafe de Bogota, Colombia
- Dr Edward Williams, FRCR, Cayman Islands, BWI
- Joe Yut, MD, Olathe, Kan
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Footnotes
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Abbreviation: ACTH = adrenocorticotropic hormone
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References
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Doppman JL, Miller DL, Dwyer AJ, et al. Macronodular adrenal hyperplasia in Cushing disease. Radiology 1988; 166:347-352.[Abstract/Free Full Text]
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Gajraj H, Young AE. Adrenal incidentaloma. Br J Surg 1993; 80:422-426.[Medline]
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Smals AGH, Pieters GFFM, van Haelst UJG, Kloppenbord PWC. Macronodular adrenocortical hyperplasia in long standing Cushing's disease. J Clin Endocrinol Metab 1984; 58:25-31.[Abstract]
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Aron DC, Findling JW, Fitzgerald JW, et al. Pituitary ACTH-dependency of nodular adrenal hyperplasia in Cushing's syndrome: report of two cases and review of the literature. Am J Med 1981; 71:302-306.[Medline]
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Orth DN. Cushing's syndrome. N Engl J Med 1995; 332:791-803.[Free Full Text]
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Doppman JL, Oldfield EH, Nieman LK. Bilateral sampling of the internal jugular vein to distinguish between mechanisms of adrenocorticotropic hormone–dependent Cushing syndrome. Ann Intern Med 1998; 128:33-36.[Abstract/Free Full Text]
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Oldfield EH, Doppman JL, Nieman LK, et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med 1991; 325:897-905.[Abstract]
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Ram Z, Shawker TH, Bradford MH, Doppman JL, Oldfield EH. Intraoperative ultrasound-directed resection of pituitary tumors. J Neurosurg 1995; 83:225-230.[Medline]
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Watson JC, Shawker TH, Nieman LK, DeVroom HL, Doppman JL, Oldfield EH. Localization of pituitary adenomas by using intraoperative ultrasound in patients with Cushing's disease and no demonstrable pituitary tumor on magnetic resonance imaging. J Neurosurg 1998; 89:927-932.[Medline]
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Schell SR, Talamini MA, Udelsman R. Laparoscopic adrenalectomy. Adv Surg 1997; 31:333-350.[Medline]
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Doppman JL, Nieman L, Miller DL, et al. Ectopic adrenocorticotropic hormone syndrome: localization studies in 28 patients. Radiology 1989; 172:115-124.[Abstract/Free Full Text]
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Vincent JM, Trainer PJ, Reznek RH, et al. The radiological investigation of occult ectopic ACTH-dependent Cushing's syndrome. Clin Radiol 1993; 48:11-17.[Medline]
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Doppman JL, Nieman LK, Travis WD, et al. CT and MR imaging of massive macronodular adrenocortical disease: a rare cause of autonomous primary adrenal hypercortisolism. J Comput Assist Tomogr 1991; 15:773-779.[Medline]
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Grant CS, Carney JA, Carpenter PC, van Heerden JA. Primary pigmented nodular adrenocortical disease: diagnosis and management. Surgery 1986; 100:1178-1183.[Medline]
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HISTORY
IMAGING FINDINGS
