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(Radiology. 2000;216:797-802.)
© RSNA, 2000

Genitourinary Imaging

Adrenocorticotropin-independent Macronodular Adrenal Hyperplasia: An Uncommon Cause of Primary Adrenal Hypercortisolism1

John L. Doppman, MD, George P. Chrousos, MD, Dimitris A. Papanicolaou, MD, Constantine A. Stratakis, MD, DSc, H. Richard Alexander, MD and Lynnette K. Nieman, MD

1 From the Department of Diagnostic Radiology, Imaging Sciences Program, Warren Grant Magnuson Clinical Center (J.L.D.), the National Institute of Child Health and Human Development (G.P.C., D.A.P., C.A.S., L.K.N.), and the Surgery Branch, National Cancer Institute (H.R.A.), National Institutes of Health, 10 Center Drive MSC 1182, Bethesda, MD 20892-1182. Received July 23, 1999; revision requested September 20; revision received November 2; accepted November 11. Address correspondence to J.L.D.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To describe the imaging findings in the adrenal glands of 12 patients with adrenocorticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH).

MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) imaging findings in the adrenal glands were reviewed retrospectively in 12 patients (three men, nine women) with ACTH-independent Cushing syndrome and with bilateral nonpigmented multinodular adrenal hyperplasia. The results of pituitary MR imaging, adrenal scintigraphy, and petrosal sampling were available in nine, five, and six patients, respectively. Eleven patients underwent bilateral and one patient underwent unilateral adrenalectomy.

RESULTS: Eleven patients had enlarged multinodular adrenal glands: Nodules were 0.1–5.5 cm. The combined weight of both adrenal specimens for the 11 bilateral adrenalectomy specimens was 28–297 g, with a mean weight of 122 g. Glands were hypointense compared with the liver on T1-weighted images and were hyperintense on T2-weighted images. Pituitary MR imaging findings were negative in nine of nine patients. Iodomethylnorcholesterol scintigraphy showed bilateral uptake in four of five patients. Petrosal sinus sampling revealed no petrosal-to-peripheral ACTH gradients before corticotropin-releasing hormone (CRH) stimulation in six of six patients, but three patients had gradients after CRH stimulation. After undergoing bilateral or unilateral adrenalectomy, all patients were cured.

CONCLUSION: AIMAH is a rare cause of ACTH-independent Cushing syndrome, with characteristic CT findings of massively enlarged multinodular adrenal glands. Bilateral adrenalectomy is indicated on the basis of clinical and CT findings.

Index terms: Adrenal gland, CT, 86.12111, 86.12112 • Adrenal gland, diseases, 86.1495, 86.541, 86.549 • Adrenal gland, hyperplasia, 86.1495, 86.541, 86.549 • Adrenal gland, MR, 86.121411 • Pituitary, MR, 145.121411, 145.12143


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The initial step in the differential diagnosis of Cushing syndrome is to distinguish adrenocorticotropin (ACTH)–dependent forms of hypercortisolism from ACTH-independent forms of hypercortisolism. ACTH dependency accounts for 80% of patients with Cushing syndrome. Of these, 85% have ACTH-secreting pituitary adenomas—Cushing disease—and 15% have ectopic ACTH-secreting tumors (1).

ACTH-independent hypercortisolism is always of adrenocortical origin. By far the most common cause (in >95% of patients) is an adrenocortical adenoma or carcinoma. Most of the remaining patients have primary pigmented nodular adrenal disease, a syndrome that is characterized by multiple small bilateral pigmented adrenocortical nodules and that often is associated with the Carney complex (2). An even rarer form of ACTH-independent primary adrenal hypercortisolism has been encountered; it consists of multiple bilateral adrenocortical macronodules that cause a striking enlargement of the adrenal glands; this is called ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) (3–18). A subset of patients with AIMAH shows ectopic expression of and/or increased responsiveness to gastric inhibitory polypeptide receptors (food-dependent hypercortisolism)(19–22), to vasopressin receptors (23–25), and to ß-adrenergic receptors (26), which suggests that the massive adrenocortical hyperplasia in these patients may be secondary to abnormalities of the receptors for various non–ACTH hormones or growth factors (27).

The computed tomographic (CT) appearance of the adrenal glands in patients with AIMAH is dramatic. Both adrenal glands are enlarged massively (combined adrenal weights are 60 to several hundred grams), with multiple macronodules up to 5 cm in diameter interspersed with multiple micronodules. The striking appearance of the adrenal glands on cross-sectional images often contrasts with the mild symptoms of hypercortisolism in many of these patients.

Most investigators report single or a few cases and stress the endocrinologic aspects of AIMAH. Swan et al (18) recently reported on a surgical series of nine patients, but investigators rarely have emphasized the unique radiologic findings. In the past 30 years, 12 patients with AIMAH were included in studies at the National Institutes of Health. The purpose of our study was to describe the CT and magnetic resonance (MR) imaging findings in the adrenal glands of 12 patients with AIMAH.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Twelve patients with ACTH-independent Cushing syndrome were examined. There were nine women and three men (mean age, 49 years; age range, 32–61 years). The diagnosis of Cushing syndrome was based on the elevation of 24-hour levels of urinary free cortisol, on a loss of normal circadian variation of the plasma cortisol level, and on the presence of typical clinical features (central obesity, striae, plethora, hypertension, etc). Eleven patients had undetectable or suppressed levels of ACTH. An ACTH assay was not available for patient 1, who was examined 35 years ago (28). In this patient, the diagnosis of ACTH-independent Cushing syndrome was based on typical clinical features, on elevated urinary levels of corticosteroids that could not be suppressed with dexamethasone, and on bilateral adrenal masses seen at radiographic retroperitoneal air insufflation.

Eleven patients underwent CT of the adrenal glands. CT scans were obtained with a model 9800 or HiSpeed Advantage (GE Medical Systems, Milwaukee, Wis) scanner. Five-millimeter-thick sections through both adrenal glands were obtained before and after an 120-mL intravenous bolus of nonionic contrast material (ioxilan; Oxilan 300; Cook Imaging, Bloomington, Ind) was administered.

Eight patients underwent MR imaging of the adrenal glands with a 0.5-T (Vista; Picker International, Cleveland, Ohio) or 1.5-T (Signa; GE Medical Systems) imager. Spin-echo T1-weighted (repetition time, 100–350 msec; echo time, 10–16 msec [100–350/10–16]; eight patients) and spin-echo T2-weighted (2,000/80–100; seven patients) transverse and coronal images were obtained without contrast material enhancement. The adrenal masses were graded as hypointense, isointense, or hyperintense compared with the liver. In-phase and out-of-phase imaging were not performed. Spin-echo T1-weighted coronal and sagittal MR images in the pituitary gland were obtained before and after the intravenous injection of 0.1 mmol/kg of gadopentetate dimeglumine (Magnevist; Berlex Imaging, Wayne, NJ) in nine patients with the 1.5-T imager.

Five patients underwent adrenal scintigraphy with 1 mCi iodomethylnorcholesterol (NP-59 [research drug]; University of Michigan). Imaging was performed 3–7 days after injection, and unilateral or bilateral uptake was recorded.

Petrosal sinus sampling was performed in six patients. Samples from both inferior petrosal sinuses were assayed for ACTH before and after intravenous stimulation with corticotropin-releasing hormone (CRH). The most recent patient (patient 12) was evaluated for receptors to non–ACTH hormones and for growth factors such as gastric inhibitory polypeptide (food-dependent hypercortisolism) and vasopressin (27). One author (J.L.D.) reviewed all CT and MR images, performed and interpreted the findings of petrosal sinus sampling, and reviewed the scintigraphic reports. The various items evaluated are noted in the Table.


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  		Clinical and Imaging Findings in 12 Patients with AIMAH
 
Eleven patients underwent bilateral adrenalectomy; patient 8 underwent unilateral adrenalectomy on the basis of unilateral NP-59 uptake. The total weight of the adrenal glands and the minimum and maximum diameters of the nodules were recorded from the pathology reports. All 12 patients experienced remission of their Cushing syndrome and were receiving glucocorticoid and mineralocorticoid replacement at the time this article was written.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The clinical and imaging features in 12 patients with surgically proved AIMAH are summarized in the Table. On CT scans, 11 patients had bilateral adrenal masses, which usually distorted and completely obscured the normal adrenal gland (Fig 1). Very large glands, such as in patient 10 (Fig 2), extended from the diaphragm down to the renal vein. The combined weight of both glands in 10 patients who underwent bilateral adrenalectomy was 28–297 g, with a mean weight of 122 g. If patient 6, who was thought to have early AIMAH, was excluded, all combined adrenal weights were greater than 60 g, with a mean weight of 132 g. Patient 11 was excluded, as her glands were only measured, not weighed. However, based on the CT appearance (Fig 3) and gross measurements, the combined weight of her glands exceeded 60 g. Patient 8 also was excluded, as she underwent unilateral adrenalectomy.



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  		Figure 1. Patient 2. Transverse nonenhanced CT scan shows multinodular adrenal glands bilaterally (arrows). The largest macronodule measured 3.8 cm. Normal, uninvolved adrenal gland could not be identified.

 


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  		Figure 2a. Patient 10. (a) The extent of adrenal enlargement (arrows) is well demonstrated on this coronal T1-weighted (300/10) spin-echo MR image. (b, c) Macronodular hyperplastic adrenal glands (arrows) are (b) hypointense relative to the liver on a transverse T1-weighted (300/10) spin-echo MR image and (c) minimally hyperintense on a transverse T2-weighted (2,000/80) spin-echo MR image.

 


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  		Figure 2b. Patient 10. (a) The extent of adrenal enlargement (arrows) is well demonstrated on this coronal T1-weighted (300/10) spin-echo MR image. (b, c) Macronodular hyperplastic adrenal glands (arrows) are (b) hypointense relative to the liver on a transverse T1-weighted (300/10) spin-echo MR image and (c) minimally hyperintense on a transverse T2-weighted (2,000/80) spin-echo MR image.

 


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  		Figure 2c. Patient 10. (a) The extent of adrenal enlargement (arrows) is well demonstrated on this coronal T1-weighted (300/10) spin-echo MR image. (b, c) Macronodular hyperplastic adrenal glands (arrows) are (b) hypointense relative to the liver on a transverse T1-weighted (300/10) spin-echo MR image and (c) minimally hyperintense on a transverse T2-weighted (2,000/80) spin-echo MR image.

 


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  		Figure 3a. Patient 11. (a) Transverse contrast-enhanced CT scan shows the medial limbs of each adrenal gland as enlarged and multinodular (arrows). (b) On a transverse contrast-enhanced CT scan obtained at a lower level, both glands show nodular involvement of the lateral limbs (arrows). Both adrenal glands extend down to the level of the renal veins.

 


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  		Figure 3b. Patient 11. (a) Transverse contrast-enhanced CT scan shows the medial limbs of each adrenal gland as enlarged and multinodular (arrows). (b) On a transverse contrast-enhanced CT scan obtained at a lower level, both glands show nodular involvement of the lateral limbs (arrows). Both adrenal glands extend down to the level of the renal veins.

 
Adrenal MR imaging was performed in eight of 12 patients: Coronal images showed the craniocaudal extent of the adrenal masses to the best advantage (Fig 2). On the T1-weighted images, all nodules were hypointense relative to the liver. On T2-weighted images, nodules were hyperintense relative to the liver in six of seven patients. The nodules in patient 5 were isointense. Pituitary MR imaging was performed in nine patients; findings were negative in all.

NP-59 scintigraphy showed bilateral uptake in four of five patients. Patient 8 had unilateral uptake but had bilateral masses. A left adrenalectomy based on the NP-59 scanning findings resulted in clinical and biochemical remission.

Petrosal sinus sampling was performed in six patients. In three patients, there were no gradients before or after CRH stimulation, but in three patients, ACTH levels were elevated four- to 18-fold above the peripheral levels after CRH stimulation. None had gradients before CRH stimulation. Gradients after CRH stimulation were thought to reflect the incomplete suppression of the normal pituitary corticotrophs through mildly or episodically elevated plasma cortisol levels rather than to reflect an ACTH-secreting pituitary adenoma.

At pathologic examination, individual nodules were 0.1–5.5 cm. A single patient (patient 5) had bilateral diffuse enlargement at CT (Fig 4); histologic examination revealed nonpigmented micronodular hyperplasia. Some patients had a dominant nodule at CT (Fig 5), but multiple smaller nodules always were present at pathologic examination.



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  		Figure 4. Patient 5. Transverse nonenhanced CT scan shows that the adrenal glands are massively but smoothly enlarged (arrows) in this 48-year-old woman with ACTH-independent Cushing syndrome. The combined adrenal weight was 149 g; histologic examination revealed multiple nonpigmented micronodules.

 


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  		Figure 5a. Patient 12. (a) Transverse contrast-enhanced CT scan shows bilateral masses (arrows) that are larger on the right in this 43-year-old woman with proved food-dependent AIMAH. (b) On a transverse contrast-enhanced CT scan obtained at a lower level, the multinodularity of the right adrenal gland (black arrows in b) is more apparent. The multinodular left adrenal gland (white arrows) also are shown. The combined adrenal weight was 169 g.

 


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  		Figure 5b. Patient 12. (a) Transverse contrast-enhanced CT scan shows bilateral masses (arrows) that are larger on the right in this 43-year-old woman with proved food-dependent AIMAH. (b) On a transverse contrast-enhanced CT scan obtained at a lower level, the multinodularity of the right adrenal gland (black arrows in b) is more apparent. The multinodular left adrenal gland (white arrows) also are shown. The combined adrenal weight was 169 g.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The unique clinical features of patients with AIMAH are the late age of onset (mean age of patients, 48 years [14], which is 10 years older than the mean age at presentation of patients with Cushing disease), and the lack of female predominance, which is evident in almost all other causes of Cushing syndrome except ectopic ACTH production. In our series, however, there was a 3:1 female predominance.

The clinical manifestations of Cushing syndrome in many patients with AIMAH are mild. This may account for the incomplete suppression of pituitary corticotrophs that leads to ACTH gradients in petrosal sinus samples after CRH stimulation. Such gradients may lead the clinician to suspect Cushing disease in spite of the suppressed ACTH levels and in spite of the normal findings at pituitary MR imaging. All three patients in our series with positive petrosal samples after CRH stimulation responded to bilateral adrenalectomy and now have normal hypothalamic-pituitary axes, which excludes the presence of an occult ACTH-secreting adenoma. In patients with classic CT findings and with suppressed serum ACTH levels, we do not recommend petrosal sampling, as the results may be misleading.

At the time this article was written, no patient with AIMAH had developed a pituitary tumor after bilateral adrenalectomy. We think that this observation is of importance, as some investigators (29) have suggested that certain cases of primary bilateral adrenal hypercortisolism may develop from long-standing Cushing disease, with a transition from ACTH dependence to ACTH independence and with suppression of the ACTH-secreting pituitary adenoma. If this hypothesis were valid, one would anticipate, at least in some cases, the reemergence of the pituitary tumor—that is, Nelson syndrome—after the normalization of serum cortisol levels. To our knowledge, this has never been described.

After undergoing bilateral adrenalectomy, most patients with AIMAH resume a normal diurnal rhythm of plasma ACTH secretion within 1 year while receiving well-controlled glucocorticoid replacement (14). This restoration of normal hypothalamic-pituitary function reinforces the theory that the primary abnormality in patients with AIMAH does not reside in the pituitary gland.

The two unique imaging features of AIMAH are the large mass of cortical tissue and the size of the individual nodules. Bilateral metastases or multiple bilateral adenomata could manifest with similar morphologic appearances, but in the presence of Cushing syndrome, this appearance is practically pathognomonic for AIMAH. Combined adrenal gland weights greater than 300 g have been reported in patients with AIMAH. The combined weight of normal adrenal glands is 8–12 g. In patients with ACTH-dependent hyperplasia and even in patients with macronodular hyperplasia (30), the total adrenal weight rarely is greater than 30 g (31). The other unique feature on cross-sectional images is the size of the largest individual nodules, which often is greater than 5 cm in diameter. As hyperplastic nodules of such size rarely are reported, these findings suggest adrenocortical adenoma or even carcinoma rather than hyperplastic nodules. Total gland weights usually are greater than 60 g, but patients with lesser total adrenal weights have been reported on (14) (Table), so there is a spectrum in this disease.

At MR imaging, the adrenal glands were hypointense compared with the liver on T1-weighted spin-echo images and also, with one exception, were hyperintense on T2-weighted spin-echo images. In-phase and out-of-phase imaging were not performed in this series of patients, many of whom underwent imaging before such pulse sequences were described. As the nodules are benign at histologic examination and are rich in lipids, one might anticipate a loss of signal intensity on the out-of-phase images, as is seen frequently in adrenocortical adenomas. However, MR imaging contributed little to the diagnosis and has not been performed in our more recent patients. Bilateral adrenal uptake of NP-59 generally is present in patients with AIMAH (14).

Histologic examination demonstrates multiple yellow macronodules in all patients. There is controversy concerning the status of the internodular uninvolved adrenal cortex. This tissue often is difficult to identify at histologic examination of these grossly distorted glands. Investigators have reported hyperplastic uninvolved cortex, a finding that favors an ACTH effect, but a few have reported normal or atrophic uninvolved cortex (14). Because of this contradiction of histologic findings, the morphology of the uninvolved adrenal cortex is not considered a criterion for the histologic diagnosis of AIMAH (14). In patients with ACTH-dependent macronodular hyperplasia associated with Cushing disease or with ectopic ACTH production, the internodular cortex is always hyperplastic (30).

AIMAH was reported recently in a mother and daughter (13). Additional cases of familial occurrence of this disease have been reported in Japan (14), and patient 7 in our series had a brother with surgically proved AIMAH. Therefore, an inherited anomaly may be suspected in at least some cases. Contrary to this hypothesis is the fact that most of the reported cases appear to be sporadic, although to our knowledge extensive family screening studies have not yet been performed.

Morioka et al (16) have reported that cortisol content and certain enzyme activities, especially enzyme P450c17, are reduced substantially in the nodules of AIMAH when compared with those of autonomous adrenocortical adenomas that produce Cushing syndrome and even when compared with normal adrenal glands. This suggests that AIMAH may cause overt Cushing syndrome because of the marked increase in the volume of the mass or in the number of cells rather than because of the overactivity of individual cortical cells. Sesano et al (32) and Aiba et al (33) also have supported this finding. Such an endocrinologic phenomenon, the autonomous overproduction of a hormone because of the total volume of the gland itself, is not unknown to clinicians. Tertiary hyperparathyroidism persisting after the normalization of renal function with transplantation may result from the mass of parathyroid tissue (secondary hyperplasia) that develops at the time of clinical renal insufficiency. The concept that endocrine tissue acquires a certain autonomy when its mass greatly exceeds normal has been suggested in several endocrinologic disorders. AIMAH may be another example of such a biologic phenomenon.

The pathophysiologic mechanism responsible for AIMAH remains obscure. Some patients have shown steroidogenic responsiveness to gastric inhibitory polypeptide or lysine vasopressin (19,21). One patient in our series (patient 12) demonstrated food-dependent hypercortisolism. Receptors to these hormones have been demonstrated in vitro with cell culture technique. It is our opinion that all patients with AIMAH should be tested to identify abnormal hormone receptors. Lacroix et al (27) have described a protocol for such investigations. However, in most patients with AIMAH, the cause of this massive macronodular hyperplasia remains obscure.

In conclusion, AIMAH manifests as enlarged multinodular adrenal glands in older patients with often mild Cushing syndrome. In our opinion, typical CT findings, with suppressed or undetectable ACTH levels, justify bilateral adrenalectomy without the need for pituitary MR imaging, NP-59 scintigraphy, or petrosal sinus sampling. Patients should undergo screening for abnormal hormone receptors, but the presence of these receptors rarely influences therapy.


   FOOTNOTES
 
Abbreviations: ACTH = adrenocorticotropin, AIMAH = ACTH-independent macronodular adrenocortical hyperplasia, CRH = corticotropin-releasing hormone, NP-59 = iodomethylnorcholesterol

Author contributions: Guarantor of integrity of entire study, J.L.D.; study concepts and design, J.L.D., L.K.N.; definition of intellectual content, J.L.D.; literature research, J.L.D., L.K.N.; clinical studies, J.L.D., D.A.P., L.K.N., C.A.S.; data acquisition, all authors; data analysis, J.L.D., L.K.N.; manuscript preparation, J.L.D., L.K.N.; manuscript editing, J.L.D., C.A.S., L.K.N.; manuscript review, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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