Department of Nuclear Medicine1) and Department of Endocrine Surgery2), Rigshospitalet, Copenhagen, and Department of Clinical Physiology3), KAS Glostrup Hospital, Copenhagen
131I-19-IODOCHOLESTEROL SCINTIGRAPHY OF THE ADRENAL CORTEX By H. Dige-Petersen1), T. Munkner1), J. Fogh1), M. Blichert-Toft2) and J. O. Lund3)
ABSTRACT
131I-19-iodocholesterol scintigraphy of the adrenal cortex has been carried out in 26 patients.
In 4 patients with normal adrenocortical function the tracer was equally accumulated on the two sides.
In 7 patients with untreated Cushing’s syndrome, bilateral uptake was found in 4 patients with bilateral hyperplasia whereas unilateral visuali- zation was obtained in three cases of cortisol producing adenomas. The side localization was confirmed at operation.
Eight patients had been operated for Cushing’s syndrome prior to the scintigraphy. Remnant adrenocortical tissue with negligible or subnormal function (4 patients) could not be visualized. Normo- or hyperfunctioning remnant tissue was visualized in 3 patients. One patient had recurrent hypercorticism due to metastases from a previously removed adreno- cortical carcinoma; a single pelvic accumulation was seen, whereas several metastases in the abdomen and thorax were not visualized.
Four patients with aldosteronism were investigated. Three had primary aldosteronism due to an adrenocortical adenoma. In two of these, the site of the adrenal lesion was localized pre-operatively. In the third patient, equal bilateral accumulation of iodocholesterol was seen even after sup- pression with dexamethasone. At operation a small tumour was found. In 1 patient with indeterminate aldosteronism both glands were visualized and at a second examination the uptake was equally suppressed by dexamethasone.
Finally 3 patients were investigated. One had a testosterone producing tumour of the right ovary. The tumour was not visualized on the scinti- gram in spite of a slight accumulation of activity as measured in vitro. Another patient with a cyst of the right adrenal gland presented a defect in the activity on the affected side. In the third patient previously sub- jected to hypophysectomy, the adrenal cortex was visualized only after ACTH-stimulation.
The 1311-19-iodocholesterol scintigraphy is a valuable method for the diagnosis and localization of cortisol and aldosterone producing tumours, and for the localization of normo- and hyperfunctioning adrenocortical remnants. The interpretation of the scintigrams must be based on relevant biochemical assays.
Several attempts have been made to synthesize a compound suitable for radio- nuclidic visualization of the adrenal cortex. Radioiodinated dichlorodiphenyl- dichloroethane (DiGiuglio & Beierwaltes 1968) and different labelled com- pounds of adrenocortical steroids, among these 131I-stigmasterol (Nagai et al. 1968), were found unsuitable for scintigraphic examinations. 125I-19-iodo- cholesterol was synthesized by Counsell et al. (1970), and scintigraphic visuali- zation of the adrenal cortex in dogs by means of this compound was described by Blair et al. (1971). Finally, adrenal scintigraphy using 131I-19-iodocholes- terol in humans was reported by Beierwaltes et al. (1971).
Studies on the in vitro decomposition of 131I-19-iodocholesterol have been performed by Hotte & Ice (1974). A radiochemical purity of at least 70 % when stored at 5℃ for 18 days has been accepted. No toxic effects of intra- venous administration of up to 20 mg of iodocholesterol have been noted.
Cholesterol enters into the biosynthesis of adrenal steroid hormones. Never- theless, the 19-iodoconfiguration has not been found in steroid metabolites in the urine of dogs (Counsell et al. 1970; Blair et al. 1971). The same in- vestigators found an adrenal to liver and adrenal to kidney ratio for the com- pound of more than 30. This favourable target to non-target ratio has been confirmed by other investigators (Morita et al. 1972). In normal adrenal glands, the uptake of 19-iodocholesterol is augmented by ACTH and suppressed by dexamethasone (Blair et al. 1971; Moses et al. 1973; Beierwaltes et al. 1974; Anderson & Beierwaltes 1974).
The whole-body radiation dose is about 0.5-1 rad/mCi 131I (Beierwaltes et al. 1971; Kirschner et al. 1973). Critical organs are the adrenal glands, the liver, and the gonads. Uptake in the thyroid gland can be avoided by administration of potassium iodide.
Clinical experience with 131I-19-iodocholesterol scintigraphy of the adrenal cortex has been increasing over the past few years (Conn et al. 1971, 1972; Lieberman et al. 1971; Morita et al. 1972; Schteingart et al. 1972; Conn & Cohen 1973; Moses et al. 1973; Anderson & Beierwaltes 1974; Sundsfjord et al.
| Code | Sex/age (years) | Diagnosis | Visualization of adrenal cortex | |
|---|---|---|---|---|
| Right | Left | |||
| I | F-53 | Normal | + | + |
| 2 | F-42 | Obesity | + | + |
| 3 | F-20 | Obesity | + | + |
| 4 | F-29 | Hirsutism Obesity Hirsutism | + | + |
1974). The purpose of the present study has been to add further information to the indications, performance, and interpretation of adrenocortical scinti- graphy.
MATERIAL
Twenty-six patients were studied.
Four patients (Nos. 1-4) (Table 1) had normal adrenocortical function. In all 4 patients, biochemical studies of adrenocortical function showed values within the normal range at the time of scintigraphy (Nielsen et al. 1969). The consent of patient No. 1 was obtained. In Nos. 2-4, obesity and hirsutism were indications for the study.
Seven patients (Nos. 5-11) (Table 2) suffered from untreated Cushing’s syndrome at the time of scintigraphy. The diagnosis was established biochemically (Nielsen et al. 1972a) and confirmed at surgery in all cases.
Eight patients (Nos. 12-19) (Table 3) were examined from 1 to 5 years after surgical treatment for Cushing’s syndrome. Residual adrenocortical function in these patients was estimated by means of the increase in urinary excretion of total corti- costerone metabolites during simultaneous ACTH-stimulation and dexamethasone (DXM) substitution (Blichert-Toft et al. 1974).
Four patients suffered from aldosteronism (Nos. 20-23) (Table 4). The biochemical diagnosis was based upon elevated excretion of tetrahydroaldosterone in urine (Nielsen et al. 1972b) and low-normal or subnormal plasma renin concentration (Giese et al. 1970). The excretion of cortisol metabolites in urine was normal (Nielsen et al. 1969). In patients Nos. 20-22, unilateral adrenalectomy revealed a single adenoma. In patient No. 23 the final diagnosis of bilateral adrenal hyperplasia (indeterminate aldosteron- ism) was based upon the normal suppressibility of aldosterone production during administration of exogenous mineralocorticoid (Biglieri et al. 1972).
Finally, 3 patients were investigated (Nos. 24-26) (Table 5): A male of 47 years
| Code | Sex/age (years) | Diagnosis | Visualization of adrenal cortex | Adrenocortical histology | |
|---|---|---|---|---|---|
| Right | Left | ||||
| 5 | F-21 | Pituitary, ACTH-dependent Cushing's syndrome | + | + | Bilateral hyperplasia |
| 6 | F-28 | Pituitary, ACTH-dependent Cushing's syndrome | + | + | Bilateral hyperplasia |
| 7 | F-36 | Pituitary, ACTH-dependent Cushing's syndrome | + | + | Bilateral hyperplasia |
| 8 | M-53 | Ectopic, ACTH-dependent Cushing's syndrome (Bronchogenic carcinoma) | + | + | Bilateral hyperplasia |
| 9 | F-36 | Cushing's syndrome, | 0 | + | Benign adenoma |
| left adrenal tumour | after removal: | (3 x 3 cm) | |||
| 0 | 0 | ||||
| 10 | F-57 | Cushing's syndrome, | 0 | + | Benign adenoma (10 x 6 cm) |
| left adrenal tumour | after | removal: | |||
| + | 0 | ||||
| 11 | F-51 | Cushing's syndrome, left adrenal tumour | 0 | + | Benign adenoma (2 x 2 cm) |
(No. 24), previously subjected to hypophysectomy due to chromophobe adenoma and subsequently substituted with thyroxine, testosterone, and cortisone acetate; No. 25, a female of 47 years who suffered from a testosterone producing tumour of the ovary; and No. 26, a female with a benign cyst of the adrenal gland. Patients No. 25 and 26 had normal adrenocortical function (Nielsen et al. 1969).
METHODS
Scintigraphy of the adrenal cortex was carried out between 5 and 21 (usually 7-10) days after intravenous injection of 1.4-2.5 mCi of 1311-19-iodocholesterol containing less than 10 mg of cholesterol per mCi 131I. The tracer was obtained from the University of Michigan, Ann Arbor, Michigan, USA, from Sorin, Saluggia, Italy,
| Code | Sex/age (years) | Diagnosis and to | surgical treatment prior scintigraphy | Adrenocortical function at the time of scintigraphy | Visualization of adrenal cortex | |
|---|---|---|---|---|---|---|
| Right | Left | |||||
| 12 | F-42 | Pituitary, | Bilateral adrenalectomy. | Negligible | 0 | 0 |
| ACTH-dependent Cushing's syndrome | Re-operation with removal of aberrant adrenal tissue | |||||
| 13 | F-47 | Pituitary, | Subtotal adrenalectomy. | Negligible | ACTH* | |
| ACTH-dependent | Re-adrenalectomy | 0 | 0 | |||
| Cushing's syndrome | ||||||
| 14 | F-50 | Cushing's syndrome. | Removal of tumour | Negligible | 0 | 0 |
| Left adrenal tumour | ||||||
| 15 | F-32 | Pituitary, | Subtotal adrenalectomy. | Subnormal | 0 | 0 |
| ACTH-dependent | Re-adrenalectomy | ACTH* | ||||
| Cushing's syndrome | 0 | 0 | ||||
| 16 | M-44 | Pituitary, | Left adrenalectomy. | Normal | + | 0 |
| ACTH-dependent | Resection of | |||||
| Cushing's syndrome | right adrenal gland | |||||
| 17 | F-23 | Pituitary, | Subtotal adrenalectomy. | Recurrent hypercorticism | ||
| ACTH-dependent | Left re-adrenalectomy | Recurrent hypercorticism | + | 0 | ||
| Cushing's syndrome | Right re-adrenalectomy | Negligible | 0 | 0 | ||
| 18 | F-61 | Pituitary, ACTH-dependent | Subtotal adrenalectomy. Left re-adrenalectomy | Recurrent hypercorticism | + | 0 |
| Cushing's syndrome | ||||||
| 19 | F-31 | Cushing's syndrome. | Removal of tumour | Recurrent hypercorticism | 0 | 0 |
| Left adrenal carcinoma | Metastases | (pelvic accumulation | ||||
| in metastasis) | ||||||
* Following stimulation with ACTH.
Si
| Code | Sex/age (years) | Diagnosis | Visualization of adrenal cortex | Adrenocortical histology | |
|---|---|---|---|---|---|
| Right | Left | ||||
| 20 | F-51 | Primary aldosteronism Right adrenal tumour | + | 0 | Adenoma (3.5 x 2.5 x 2 cm) microinvasive growth, malignant?) |
| 21 | F-39 | Primary aldosteronism | DXM+ | Benign adenoma (1.5 x 1.5 x 1 cm) | |
| Left adrenal tumour | (+) | + | |||
| 22 | F-52 | Primary aldosteronism | + | + | Benign adenoma |
| Left adrenal tumour | DXM* | (0.5× 1 × 1 cm) | |||
| (+) | (+) | ||||
| 23 | M-49 | Indeterminate | + | + | (not operated) |
| aldosteronism | DXM* | ||||
| 0 | 0 | ||||
* Following suppression with dexamethasone.
| Code | Sex/age (years) | Diagnosis | Visualization of adrenal cortex | |
|---|---|---|---|---|
| Right | Left | |||
| 24 | M-47 | Hypophysectomy (chromophobe adenoma) | 0 | ACTH 0 |
| + | + | |||
| 25 | F-47 | Testosterone producing Leydig cell tumour of right ovary | DXM | |
| (adrenal and ovary) | ||||
| 0 | 0 | |||
| 26 | F-50 | Cyst of right adrenal gland | (+) | + |
and in a few cases from the Institute of Atomic Energy, Kjeller, Norway. No adverse reactions were noted. The tracer was injected slowly intravenously with 20 ml of isotonic saline, injection time about 2 min.
The scintigraphy was in most cases performed by means of a rectilinear scanner (Ohio Nuclear) with two 8” Nal (Tl)-crystals. The collimators had a focal distance of 12.7 cm. In a few instances, a gammacamera was used alone or for supplementary scintigrams (ND 50/50 Radicamera, Selektronic, Denmark, or a Nuclear Chicago Pho-Gamma HP III). A scan of the adrenal region (anterior and posterior views), or if necessary of a wider area was made. Accumulation of radioactivity in the bowel was frequently observed in early scans. If necessary, an enema was given, and the scan was repeated a few days later. The thyroid gland was blocked by administration of 15 ml of 3.3% potassium iodide solution. When iodide is given at least half an hour before and once daily after the injection of the tracer, no uptake of 1311 in the thyroid can be traced.
Stimulation of the adrenal cortex with ACTH prior to scintigraphy was carried out as follows: 1 mg of Synacthen Depot® was administered intramuscularly daily from about 1 week prior to the injection of iodocholesterol and until the day of scinti- graphy. Furthermore, short ACTH stimulation test was carried out post-operatively in patients with cortisol-producing adenoma in order to check whether the function of the contralateral adrenal cortex was restored. 0.25 mg Synacthen® was given intra- venously as a single dose. Blood samples for 11-hydroxycorticosteroid determination were drawn before and 30 and 60 min p. i.
Suppression of the adrenal cortex with DXM prior to scintigraphy was performed by giving 0.5 mg DXM every 6 h from 3 days prior to the injection of iodocholesterol and until termination of the scintigraphy.
RESULTS
The scintigraphic results are enlisted in Tables 1-5. Examination with a gammacamera did not add new details to the information obtained by a recti- linear scanner.
In patients with normal adrenocortical function (Table 1), equal distribution of activity on the two sides was seen.
In 4 of 7 patients with untreated Cushing’s syndrome (Table 2), the pre- operative scintigrams showed identical uptake of iodocholesterol on the two sides (Fig. 1). At operation both glands were found to be hyperplastic. In 3 patients unilateral accumulation of activity was seen, corresponding to adenomas found at operation (Fig. 2). In patient No. 9, a post-operative scan showed no accumulation on the contralateral side, in accordance with no biochemical response to short ACTH-stimulation. At operation, the contra- lateral gland was visualized and found to be normal by external examination. In patient No. 10, the radioactive concentration in the removed tumour was measured in vitro. Tumour to blood ratio varied between 30:1 and 12:1, the latter in necrotic areas corresponding to a large irregular tumour on the scinti-
granm. In this patient post-operative scintigrams showed accumulation of radio- activity on the contralateral side, indicating restored function of the remaining adrenal cortex. This finding was in accordance with a positive biochemical response to short ACTH-stimulation test.
The data of the 8 patients examined 1 to 5 years after surgery for Cushing’s syndrome are listed in Table 3. In 3 patients (Nos. 12-14) with negligible, and in one (No. 15) with subnormal function, residual adrenocortical tissue
could not be visualized by scintigraphy, in two of them not even 1 week after ACTH-stimulation (Nos. 13 and 15). However, in one patient with normal adrenocortical function following surgery (No. 16) and in 2 patients with recurrence of Cushing’s syndrome following surgery (Nos. 17 and 18), remnant tissue could be localized by scintigraphy. Patient No. 17 (Fig. 3) was re- operated. and an adrenocortical remnant was removed from behind the inferior
caval vein. After this third operation, no radiocholesterol uptake could be traced. In patient No. 19 with metastases from an adrenocortical carcinoma, accumulation of iodocholesterol was seen only in one of the metastases in the abdomen, although several tumour masses were found in the abdomen at surgery, and although the chest X-ray indicated metastases in both lungs.
The scintigraphic results of the patients with aldosteronism are shown in Table 4. Patient No. 20 had accumulation of activity in the right adrenal cortex. and at operation an adenoma was found on this side. In patient No. 21,
the cortex of both adrenal glands was visualized in spite of suppression with DXM. However, a significant difference between the two sides was evident, and an adenoma was found in the gland corresponding to the greatest activity. In patient No. 22 no difference between the two sides could be demonstrated, neither before nor after DXM suppression. Nevertheless a small tumour (0.5 x 1 x 1 cm) was found in the left adrenal gland. The right adrenal gland appeared normal at inspection and palpation. The fact that the excretion of tetrahydroaldosterone and plasma renin concentration were normalized after operation, seems to exclude the presence of an aldosterone-producing tumour in the contralateral gland. Patient No. 23 had equal activity on the two sides and no iodocholesterol uptake after DXM suppression. Bilateral adrenocortical hyperplasia has been considered most likely in this patient.
Three patients are listed in Table 5. In the hypophysectomized patient treated with cortisone (No. 24), normal adrenal glands were visualized only after stimulation with ACTH (Fig. 4). Patient No. 25 showed normal suppressibility during DXM administration corresponding to no adrenal uptake on the scinti- gram. The testosterone-producing tumour (3 x 3 cm) of the right ovary was not visualized by the scintigraphy performed during DXM suppression. How- ever, post-operative in vitro measurements showed that the ratio between countrates in tumour tissue and blood was 2:1, and in tumour to normal ovarian tissue 5:1. Patient No. 26 had a defect in the right adrenal cortex on the scintigram, corresponding to the site of a cystic lesion (3 x 4 cm). By post-operative in vitro measurements the ratio between activities in normal adrenal tissue to blood was found to be 200:1. Cyst fluid contained less activity than blood.
DISCUSSION
The purpose of the present study has been to localize an adrenocortical lesion which had already been biochemically and/or otherwise diagnosed. No attempts were made to obtain quantitative information of the function of the adrenal cortex or tumour by measuring the uptake of 1311-19-iodocholesterol.
Quantitative studies have been carried out by other investigators. An exact measurement of adrenocortical uptake, however, is difficult. Adrenal countrate is low, only about 0.1 % of the dose is accumulated in a normal adrenal gland (Morita et al. 1972; Beierwaltes et al. 1974; Conn et al. 1971; Lieberman et al. 1971). Background countrate is relatively high due to activity in the bowels and liver. Furthermore variations in adrenocortical distance from the detector (adrenal depth) necessitates an individual correction for gamma ray absorption in tissues (Morita et al. 1972). In spite of these difficulties, a higher than normal uptake has been found in all patients with ACTH-dependent Cushing’s
syndrome (Morita et al. 1972; Lieberman et al. 1971). In unilateral aldosterone producing tumours an uptake ratio of more than two between the tumour and non-tumour side has been reported (Conn et al. 1971, 1972). This seems to exceed the normal difference significantly (Beierwaltes et al. 1974). There- fore, measurements of uptake may prove to be useful in patients with aldo- steronism. According to Anderson & Beierwaltes (1974) dexamethasone sup- pression will in most cases of aldosteronism caused by a unilateral tumour make the difference evident on the scintigram so that quantitation becomes unnecessary. Nevertheless, in our study one of three aldosterone producing tumours (No. 22) was missed in this way, but the tumour was very small, about 1 cm in diameter.
Based on our study and on the literature the present experience with 1311- 19-iodocholesterol scintigraphy may be evaluated as follows:
In Cushing’s syndrome a differentiation between ACTH-dependent adreno- cortical hyperfunction and unilateral adenomas, including a side-localization of the latter, can be achieved regularly. It should be noted, however, that Beierwaltes et al. (1974) reported two cases of suspected adrenocortical adeno- mas with no biochemical evidence of Cushing’s syndrome. No 131I-19-iodo- cholesterol uptake was observed in the contralateral gland as is the case with hyperfunctioning adenomas. One adenoma was suppressible with dexame- thasone, one was not. It is suggested that these adenomas could be similar to functioning non-toxic thyroid nodules. However, the scintigraphic findings were not verified by surgery and thus a complete explanation has not been obtained.
In Cushings syndrome due to adrenocortical carcinoma, whether previously untreated or recurrent, tumour tissue is in most cases not visualized (Forman et al. 1974; Lieberman et al. 1971). Anderson & Beierwaltes (1974) found a very low concentration of radioactivity per g tumour tissue. The excess cortisol production may take place in a large mass of poorly functioning adrenocortical carcinoma.
An important use of 1311-19-iodocholesterol scintigraphy is the localization of remnant adrenocortical tissue after bilateral adrenalectomy. In our study, the results of scintigraphy correlated very well with the adrenocortical function of the patients. In the cases of negligible or subnormal function, no adreno- cortical tissue could be visualized, whereas normo- or hyperfunctioning tissue was invariably seen. Furthermore, in the patients operated for unilateral adenomas causing Cushing’s syndrome, the post-operative scans correctly indicated whether the function of the contralateral gland was restored or not.
In aldosteronism unilateral tumours can be localized. The difference between the uptake in the tumour-bearing gland and the normal gland may be enhanced during dexamethasone suppression. However, in our study only one of three tumours was clearly visualized, and one was missed in spite of dexamethasone
suppression. In case of bilateral tumours the interpretation of the scintigrams is probably difficult.
Phaeochromocytomas and non-endocrine adrenal tumours may, according to their size and localization cause more or less destruction of the normal adrenocortical tissue, and therefore be recognized as “cold” areas on the scinti- grams (Sturman et al. 1974; Anderson & Beierwaltes 1974).
Virilizing tumours of the adrenal glands may be localized as “cold” areas on the 131I-19-iodocholesterol scintigrams. Anderson & Beierwaltes (1974) re- ported one patient with a testosterone producing adrenocortical tumour which did not concentrate iodocholesterol, whereas the contralateral gland appeared normal on the scintigram. Our patient with a testosterone producing tumour of the ovary was examined during dexamethasone suppression. Accordingly, the adrenal cortex was not visualized, nor was the ovarian tumour although a moderate accumulation of activity was found in the tumour by counting in vitro. So far, a “positive” scintigraphic visualization of virilizing tumours has not been performed.
The 131]-19-iodocholesterol scintigraphy of the adrenal cortex has proven its clinical usefulness. It is non-invasive, causes no risk or discomfort to the patients, and it may be carried out on out-patients. Hence, it should be the method of first choice for localization studies both in Cushing’s syndrome and in hyperaldosteronism, provided that the interpretation of the scintigram is based on relevant biochemical assays.
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Received on October 7th. 1974.