Adrenal scintigraphy in Cushing’s syndrome caused by bilateral hyperplasia, adenoma or carcinoma
S. LINDBERG1, I. ERNEST2, M. FJÄLLING1 and C. HOLMDAHL 1
1Division of Nuclear Medicine, Department of Diagnostic Radiology, and 2Division of Endocrinology, Department of Internal Medicine, University of Göteborg, Sweden
Received 24 July 1984
Summary
The results of scintigraphy in 29 patients with Cushing’s syndrome were evaluated. It was possible to separate bilateral hyperplasia from unilateral abnormality. In cases of unilateral abnormality correct localization of the tumour was accomplished and it was possible to visualize adrenocortical carcinoma. The many advantages of adrenal scintigraphy are listed and it is concluded that adrenal scintigraphy is the best means of investigation to differentiate between ACTH-dependent and ACTH-independent Cushing’s syndrome.
Introduction
In the past retroperitoneal air insufflation, adrenal venography and arteriography have been used to localize the adrenals and to diagnose adrenal tumours.
In 1971, Beierwaltes [1] described the visualization of the adrenal glands by adrenal scintigraphy of a patient with Cushing’s syndrome after administration of 1311-19-iodocholesterol. Three years later Beierwaltes [2] published a review of adrenal imaging in 100 patients. He showed that adrenal scintigraphy is as efficient as venography in visualizing the adrenals and also stressed that adrenal scinti- graphy is without the hazards of invasive procedures. Beierwaltes meant that the test, which is highly accurate, should be used as a screening method, especially because it is noninvasive, nontraumatic and requires no hospitalization.
Reports of CT being the most favoured means of examining patients with adrenal
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dysfunction [3-5] caused us to see the necessity of publishing our experience of adrenal scintigraphy in patients with Cushing’s syndrome.
The present study summarizes our experience of 29 patients with Cushing’s syndrome. In our department adrenal scintigraphy has been used not as a screening method, but as a method of determining the types of abnormality that caused the adrenal dysfunction.
Material and methods
Patients
Between 1973 and 1980, 96 adrenal scintigraphies were performed at the Division of Nuclear Medicine, Department of Diagnostic Radiology, at Sahlgrenska Hospital in Göteborg. Of the 96 scintigraphies, 29 were performed on patients with Cushing’s syndrome. The 29 patients, 25 women and 4 men, in the present study were between 26 and 77 years old when in- vestigated. Before being sent to us for scintigraphy, all the patients underwent a thorough endocrinological investigation at the Department of Endocrinology. The diagnosis of Cushing’s syndrome was based on a typical clinical appearance and typical laboratory findings of ACTH production, cortisol secretion rate, and urinary excretion of free cortisol. Some patients underwent the Metyrapone test after having undergone scintigraphy.
Scintigraphy
The scintigraphy was carried out with an Anger camera, Nuclear Chicago Phogamma HP, equipped with a high sensitivity home-made 200 hole collimator, the resolution of which was improved by rotation and optical image reconstruction.
1311-19-Iodocholesterol was used as the radiopharmaceutical. Being a precursor to adreno- corticol hormones, cholesterol is accumulated in the adrenal cortex. A dosage of 0.2 MBq 1311-19-iodocholesterol/kg body weight was given i.v. Immediately prior to the administration of the radionuclide, 150 mg potassium iodine was given orally to block the thyroid gland and this medication was continued for eight days. Four to ten days (commonly 5-6 days) after administration of the radionuclide, scintigraphy was performed with the patient in the prone position and the camera positioned over the patient giving posterior-anterior views. Uptake of radionuclide was registered in a computer and static polaroid pictures were taken simul- taneously. By background subtraction, fractional uptake in the adrenals could be calculated. Uptake of radionuclide was unilateral or bilateral.
Results
Unilateral uptake
Thirteen patients, 11 women and two men, had unilateral uptake indicating an ACTH-independent Cushing’s syndrome. In 10 of these 13 patients the uptake was judged to be caused by an adenoma (Fig. 1). Laboratory tests supported the diag- nosis of adrenocortical adenoma, which was proved by operation and subsequent complete clinical remission. The extirpated tumours weighed between 9 g and 65 g.
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In the remaining three patients with unilateral uptake adrenocortical carcinoma was suspected as the uptake was large and not very intense (Fig. 2). Later operation and microscopic examination of the tumours confirmed the diagnosis, the tumours being large (220 g, 300 g, 375 g) with intravascular tumour growth and distant metastases. The clinical course was aggressive, all three patients dying within a year of diagnosis.
displayed a unilateral, large and not very intense uptake, an image not observed in the adenomas (Figs 1, 2). This uptake pattern is due to a low concentration of tracer dose/g tissue in a large tumour [6, 7]. That adrenal carcinomas do not always accumulate enough radiocholesterol to be visualized by scintigraphy is clear from the findings of others [2, 8]. Significant uptake has not been demonstrated by them either in the carcinoma or in the normal adrenal tissue. Although such a finding does not indicate the site of the lesion, it certainly demonstrates the presence of an autonomously functioning adrenal gland, causing suppression of normal adrenal tissue. In a case of adrenocortical carcinoma, not included in this study because of the absence of Cushing’s syndrome, we found uptake only in the normal adrenal gland. This is in accordance with the experience of Sarker [9].
In a patient suffering from ACTH-independent Cushing’s syndrome and present- ing the clinical picture of hypercortisolism, enough cortisol should be produced to extinguish pituitary ACTH secretion. In cases of carcinoma unilateral uptake or nonvisualization of the adrenals is to be expected [2, 7, 8]. In our patients as well as in those discussed by others [8, 10] adrenal adenomas causing Cushing’s syndrome were always active enough to be visualized by scintigraphy.
Scintigraphy has not been a successful method for reliably differentiating patients with ACTH-dependent Cushing’s syndrome from normal subjects [10]. In our patients the fractional uptake of radiocholesterol in cases of Cushing’s disease was sometimes elevated. Overlapping with that of normal persons was seen in too many cases to render percentage uptake a useful means of differentiating between normal subjects and those with Cushing’s disease. Nor was there any difference between the percentage uptake in patients suffering from Cushing’s disease and that of those suffering from ectopic ACTH secretion.
A diagnosis of Cushing’s syndrome is suspected on clinical grounds. Laboratory tests confirm the suspicion and are usually capable of differentiating between Cushing’s disease on the one hand and cortisol- and ACTH-producing nonpituitary tumours on the other. The Metyrapone test is an especially valuable tool as the secretion of adrenal steroids is always stimulated by this enzyme inhibitor in cases of Cushing’s disease, never in patients with cortisol-producing tumours and only rarely in subjects harbouring ACTH-secreting nonpituitary tumours. Adrenal scintigraphy is very effective in the diagnosis and localization of cortisol-producing tumours, leaving the differentiation between Cushing’s disease and ectopic ACTH production to other considerations. As scintigraphy is noninvasive and does not expose the patient to an inordinate amount of radioactivity or toxic contrast material it must be considered the most favourable means of investigation.
References
1. Beierwaltes HW, Lieberman ML, Ansari NA et al. Visualization of human adrenal glands in vivo by scintillation scanning. JAMA 1971; 216: 275.
Bilateral uptake
Sixteen patients, 14 women and two men, had bilateral uptake on scintigraphy (Fig. 3) indicating an ACTH-dependent Cushing’s syndrome. In 12 patients the peroral administration of Metyrapone for two days induced a marked increase in the urinary excretion of 17-hydroxy-corticosteroids. These subjects had Cushing’s disease and all except one had excellent clinical remission after bilateral adrenalectomy showing hyperplasia in all cases. One older woman underwent total hypophysectomy and also enjoyed a complete remission.
Four patients with bilateral uptake did not increase the urinary excretion of cortisol metabolites after Metyrapone and were presumed to have the ectopic ACTH syndrome. Three of these patients had malignant tumours (oat-cell cancer of the lung, hepatoma with multiple hepatic metastases and a carcinoid tumour of the lung) and two of them underwent bilateral adrenalectomy and improved after the removal of hyperplastic adrenals but succumbed within a few months to the malignant disease. The third died after pulmonectomy. Portmortem examination showed bilateral adrenal hyperplasia and metastases from carcinoid.
In the fourth subject with suspected ectopic ACTH production, Cushing’s syndrome disappeared after resection of a carcinoid tumour of the ileum; she remains healthy five years after her operation. She needed to take cortisone acetate for several months after surgery because of adrenal insufficiency.
Percentage uptake
The calculated percentage uptake of 1311-19-iodocholesterol in the adrenal glands could not be evaluated reliably enough to distinguish either between pituitary and nonpituitary etiologies of bilateral hyperplasia or between normal and elevated bilateral uptake.
Discussion
In cases of ACTH-independent Cushing’s syndrome, uptake of radiocholesterol is to be expected mainly in the cortisol-producing tumour due to inactivity of normal adrenal tissue, following suppression of ACTH secretion. In ACTH-dependent Cushing’s syndrome, uptake should occur in both hyperactive adrenal glands. In our patients scintigraphy consistently indicated the presence of cortisol-producing tumours and thus correctly differentiated ACTH-independent from ACTH- dependent Cushing’s syndrome.
It is well known that adrenal carcinomas are generally larger than adenomas on diagnosis. The overlap, however, is great. Also smaller tumours eventually show their malignant potential by recurring after surgery, sometimes after many years. Even histological examination cannot reliably exclude cancer in favour of adenoma. The scintigraphic image obtained in the three adrenal carcinomas in our series