The scintigraphic localization of mineralocorticoid-producing adrenocortical carcinoma1
Y. Shenker*, M.D. Gross ** , R.J. Grekin*, S.G. Rosen*, J.A. Sanfield*, B. Shapiro ** , B. Samuels *** , W. Strodel **** , N.W. Thompson **** , T.F. Beals ***** , and R.V. Lloyd’ *The Department of Internal Medicine, Divisions of Nuclear Medicine ** and Endocrinology and Metabo- lism*, the Department of Radiology *** , the Department of Surgery **** and the Department of Patholo- gy ***** , The Veteran’s Administration and The University of Michigan Medical Centers, Ann Arbor, Michigan 48105, USA
ABSTRACT. I-131-63-iodomethylnorcholesterol (NP-59) was used to localize mineralocorticoid- secreting adrenocortical carcinomas in two patients and functioning metastases in a third patient studied after the removal of the primary tumor. The presence of sufficient NP-59 activity within these lesions for discernable imaging is unusual and would not have been expected based on previous experience with other functioning and nonfunctioning carcinomas of the adrenal cortex. These cases serve to illustrate the variable spectrum of iodocholesterol uptake into adrenocortical malignancies and suggest that scintigraphic studies, preoperatively for localization and postop- eratively to confirm the presence of recurrence or metastases, might be useful to identify and characterize these rare neoplasms.
INTRODUCTION
Functioning adrenocrtical carcinomas are uncommon. Studies indicate that less than one percent of all adre- nal lesions are malignant and of these neoplasms the least common is the mineralocorticoid-secreting adre- nal tumor (1, 2). These lesions are functionally charac- terized by the well recognized biochemical findings of a low or suppressed plasma renin activity (PRA) and elevated levels of pre-aldosterone and aldosterone metabolites in both plasma and urine; hypokalemia, metabolic alkalosis and elevated urinary 17-ketoste- roid levels are other biochemical manifestations asso- ciated with these lesions (1-13). Common to all adre- nocortical malignancies, whether they secrete gluco- corticoids, androgens and/or mineralocorticoids, is that they usually manifest as a marked enlargement of the adrenal (2). The scintigraphic evaluation of such suspected malignant lesions has previously been re- ported as unsuccessful (14).
The present report demonstrates that in three patients with primary aldosteronism due to this rare malignancy, sufficient I-131-63-iodomethylnorcholesterol (NP-59)
1 Supported by grants from: NCI (CA-09015), the NIAMDD RO1-AM-21477RAD, the General Clinical Research Center HEW 3M01 RR 00042-21 S1 CLR NHLBI (HL- 18575) the Veteran’s Administration Research Service and the Nuclear Medicine Research Fund.
B.S .** is the recipient of a National Institutes of Health Clinical Associate Physician Award.
Key-words: Adrenal, mineralocorticoid, carcinoma, scintigraphy, iodocholesterol.
Correspondence: M.D. Gross, M.D (115) Nuclear Medicine Service, Veteran’s Admin- istration Medical Center, 2215 Fuller Rd., Ann Arbor, Michigan 48105, USA.
Received December 31, 1984, accepted January 27, 1986.
accumulation was observed within the primary adrenal lesion in two patients and in the metastases of a third patient for discernable imaging and localization.
MATERIALS AND METHODS
One mCi of I-131-63-iodomethylnorcholesterol (NP- 59) was injected into each patient. Two patients (Cases 1 and 3) were studied under basal conditions, while a third (Case 2) received dexamethasone, 4 mg daily in divided doses for 7 days prior to and for 5 days follow- ing iodocholesterol administration (15). Lugol’s solu- tion of SSKI, 2-3 drops twice daily was administered for 24 h prior to NP-59 administration and for 1 week thereafter to block the thyroidal uptake of free I-131 iodine (15). Anterior, posterior and lateral scintiscans were obtained on days 3 through 5 after NP-59 admin- istration using a gamma camera (Searle pho Gamma IV or Ohio Nuclear 110) interfaced to a digital mini- computer (MDS-Modumed or MDS-A2). At least 50,000 counts per image were collected for each view ob- tained.
All biochemical studies were performed prior to the imaging procedures. Serum sodium and potassium were measured by autoanalyzer. Urinary 17-hydroxy- corticosteroids, 17-ketosteroids were measured by fluorometry while urinary-free cortisol, plasma renin activity, desoxycorticosterone (DOC), progesterone, corticosterone, DHEA, pregnenolone and plasma and urinary aldosterone were measured by radioimmu- noassay.
Case 1
A 47-year-old woman was admitted for weakness and
a gait disturbance. Hypertension had been previously noted and treated intermittently with diuretics, while the new onset of ventricular arrhythmias had been noted. On admission the serum potassium was 1.6 mEq/l (normal 3.5-5.5 mEq/l), serum sodium was 150 mEq/I (normal range 135-145 mEq/l) and blood pressure was 200/118 mmHg. Spironolactone and supplemen- tal potassium increased serum potassium to 2.6 mEq/1. Later while off spironolactone and on an unrestricted sodium intake urinary aldosterone was 172 ug/day (normal < 17 µg/day) with a plasma renin activity which was 0.45 ng/ml/h (normal 2-5 ng/ml/h). An adrenal venogram demonstrated a right adrenal mass
and at laparotomy a benign-appearing right adrenal tumor was resected. Histologic evaluation revealed an adrenal tumor with solid trabeculi of glomerulosa cells containing scanty eosinophilic cytoplasm. Cellular plemorphism with nuclei and mitotic figures were also noted. A postoperative iodocholesterol scan (Fig. 1C) (non-dexamethasone suppressed) demonstrated the remaining left adrenal and areas of abnormal, focal uptake in the lower chest and the liver. Subsequent studies including a Technetium-99m sulfur-colloid li- ver-spleen scan confirmed the presence of tumor with- in the liver (Fig. 1A, 1B). Abdominal re-exploration demonstrated liver metastases. Therapy with spirono-
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Fig. 1 - Anterior (A) and right lateral (B) Technetium-99m sulfur colloid liver scans depict the areas of metastases as “cold” defects (arrows). Postoperative iodocholesterol scan (C) taken 5 days post injection (anterior projection). The left adrenal is visualized (large arrow) as are the metastases in the liver and lower thorax (small arrows).
lactone, supplemental potassium and adrenal che- motherapeutic agents (Op’DDD) was continued, but the patient expired six months later.
Case 2
A 43-year-old male was admitted for evaluation of bi- lateral calf pain. His previous history was remarkable for long standing hypertension which had been poorly controlled. Eighteen months prior to admission the pa- tient had been evaluated for syncope and profound hypokalemia with serum potassium levels of 2.3 mEq/I and serum sodium levels of 145 mEq/I. On admission thiazide diuretics were discontinued and the patient was treated with iv potassium. Subsequently he main- tained normal potassium levels without replacement. On subsequent readmission the patient was again found to be hypertensive with a potassium level of 2.6 mEq/I. Renal angiography showed mild to moderate nephrosclerosis without renal artery stenosis. Howev- er, a large, round, soft tissue density mass lesion was found superior to the upper pole of the right kidney. Table 1 outlines the pertinent preoperative endocrine studies. Based upon biochemical features of hypo- kalemia, hyporeninemia, elevated urinary aldosterone excretion and hypertension, a diagnosis of primary al- dosteronism was confirmed.
Computed tomography demonstrated a 4 x 4 cm mass in the region of the right adrenal (Fig. 2A). A preopera-
tive dexamethasone suppression adrenal scintiscan confirmed the presence of unilateral, early accumula- tion of NP-59 in the right adrenal (Fig. 2B, 2C). The left gland was not identified in any of the images. A 4 x 5 cm mass was resected and the histology revealed a typical adrenocortical tumor (Fig. 3). The tumor consisted of a mixture of large clear cells easily recognized as an adrenal cortical neoplasm, smaller cells with large ovoid nuclei and denser cytoplasm and pleomorphic large cells with bizzare nuclei and eosinophilic cyto- plasm. Using recently described criteria for the evalua- tion of adrenal cortical tumors this was a grade 5 ma- lignant neoplasm (16). A pesistent, postoperative ele- vation of deoxycorticosterone levels was noted (30 ng/dl) and treatment with Op’DDD was started; at the present time the patient remains normokalemic and normotensive and repeated NP-59 abdominal imaging has been normal.
Case 3
A 54-year-old woman was admitted with complaints of headaches, hypertension and severe hypokalemia. Six months previously she was noted to have a random serum potassium of 1.8 mEq/L. On admission blood pressure was 220/100, there was slight bilateral disc- blurring on the fundoscopic examination and a low- pitched systolic murmur was evident at the ·cardiac apex. There were no palpable abdominal masses and
| Units | Normal Range | Case 2 | Case 3 | |
|---|---|---|---|---|
| Urine Catecholamines | ||||
| Norepinephrine | (ug/24 h) | (30 ± 30) | 45 | 17 |
| Epinephrine | (ug/24 h) | (8± 7) | 0.7 | 0.4 |
| Metanephrine | (ug/24 h) | (33 ± 16) | 28 | 32 |
| Normetanephrine | (ug/24 h) | (44 ± 40) | 64 | 12 |
| Vanylmandelic acid | (ug/24 h) | (< 7000) | 3200 | 1200 |
| Urine Steroids | ||||
| 17-hydroxy-corticosteroids | (mg/24 h) | (3-12) | 16.5 | 7.7 |
| 17-ketosteroids | (mg/24 h) | (10-20) | 14.5 | 25 |
| Aldosterone | (ug/24 h) | (2-20) | 34.0 | 371 |
| Free cortisol | (ug/24 h) | (20-90) | -- | 115 |
| Blood | ||||
| Aldosterone (supine) | (ng/dl) | (4.9 - 25.4) | 24.8 | 152.3 |
| PRA (supine) | (ng/ml/h) | (0.8 - 4.0) | 0.2 | 0.2 |
| PRA (upright) | (ng/ml/h) | (1.0 - 11.3) | 0.3 | 0.4 |
| Cortisol (morning) | (g/dl) | (10 - 25) | 11.6 | 27 |
| ACTH | (pg/ml) | (60-90) | 33.0 | 40 |
| Progesterone | (ng/ml) | (0.1 - 1.1) | 0.3 | |
| Corticosterone | (ng/dl) | (110 - 810) | 584 | 808 |
| DHEA | (ng/dl) | (160 - 700) | 64.2 | 809 |
| Pregnenolone | (ng/dl) | (60 - 180) | <60 | |
| DOC | (ng/dl) | (2 - 13) | 20 | 21 |
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slight pedal edema was appreciated. Serum sodium was 143 mEq/I and potassium was 2.5 mEq/L. The chest x-ray showed cardiac enlargement but was oth- erwise normal. Blood pressure was controlled with iv nitropruside and oral hydralazine. Computed tomo- graphy depicted an 11 x 10 x 7 cm mass in the region of the right adrenal and retrohepatic area that displaced the inferior vena cava laterally and the right kidney inferiorly (Fig. 4 C). Table 1 outlines the salient preop- erative endocrine studies in this patient. An adrenal NP-59 scan showed accumulation of the radiotracer into the right-sided mass and the normal left adrenal
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cortex (Fig. 4A). A large 11 x 11 cm mass that indented the posterior surface of the liver and invaded the infe- rior vena cava was resected. Microscopic examination of the tumor was considered to be typical of an adreno- cortical malignancy with large pleomorphic cells, intra- tumoral necrosis and numerous mitotic figures. Pos- toperative urinary aldosterone had fallen to 7.3 ug/D, DOC levels remained in the 20 ng/dl range, and a repeat NP-59 scan demonstrated the absence of the right adrenal activity (Fig. 4B). The left adrenal gland was again evident and there were no abnormal collec- tions of the radiotracer seen elsewhere.
DISCUSSION
The diagnosis of mineralocorticoid excess is estab- lished by the presence of hypertension, hypokalemia, elevated plasma or urinary aldosterone or other aldo- sterone metabolites and suppressed plasma renin ac- tivity (17, 18).
Adrenal cortical carcinoma rarely causes mineralocor- ticoid excess. Less than 5% of low renin hyperaldo- steronism is caused by a malignant adrenal tumor (1). In fact only about 30 cases of adrenal carcinoma with mineralocorticoid excess have been reported (1-13), most were due to aldosterone excess but some were a result of excessive aldosterone precursor production (10-13). In some cases the clinical picture was that of combined Cushing’s syndrome and mineralocorticoid excess due to elevated deoxycorticosterone (12, 13). The differentiation of adenoma from carcinoma in the absence of metastases may be difficult. The histologi- cal grading system of Weiss et al. is useful in making this distinction, 18 of 19 tumors graded 4-9 either re- curred or metastasized (16). Patient 2 has a grade 5 tumor and together with persistent, abnormal DOC lev- els this strongly supports a diagnosis of malignancy. Once the biochemical diagnosis is established, the source of abnormal secretion can be localized nonin- vasively using ultrasonography, computed tomography (CT) and adrenal scintigraphy. Both CT and scintig- raphy have demonstrated efficacy in the identification of adrenal tumors, however, scintigraphy is unique as it provides the additional information of function (15). The absence of discernible NP-59 accumulation into an enlarged adrenal in a patient with demonstrable hor- mone excess, strongly suggests the possibility of car- cinoma (14-15). Occasional reports of both primary and metastatic adrenal lesions showing significant NP-59 uptake sufficient for imaging have been pub- lished (19-24). In these instances, functioning and non- functioning adrenocortical carcinomas, either cortisol, androgens or their metabolites, may be found to be elevated in blood and urine (19-23). However in only one of these cases has mineralocorticoid excess been present. Studies of tumor accumulation of the radio- cholesterols have demonstrated uptake into carci- nomatous tissues, but in comparison to either the nor- mal adrenal cortex or functioning adenomas, the up- take is usually less by an order of magnitude (14). This supports the contention that the uptake per gram of radiocholesterol by malignant tumors is too low for imaging (14). Alternative explanations for this observa- tion could be rapid metabolic turnover or dehalogena- tion of the radiotracer, but neither of these two possibili- ties have as yet been confirmed.
Localization by CT and adrenal vein hormone sampling of an adrenocortical carcinoma resulting in primary aldosteronism has been reported by Grim et al. (9). This tumor did not accumulate sufficient NP-59 for discern- ible imaging, but the absence of tumoral and contralat- eral adrenal gland visualization does suggest that a
functioning malignancy was responsible for the bio- chemical abnormality. Furthermore, in case reports by Greathouse, et al. and Sakashita, et al. malignant-ap- pearing adrenocortical aldosterone-producing tumors were imaged with NP-59 (25, 26). The three cases noted in the present study, all demonstrating NP-59 uptake into functioning adrenal tumors, suggest that there is a spectrum of adrenocortical mineralocorti- coid-secreting neoplasms that differ in their avidity for NP-59. The uptake of radiocholesterol by the function- ing metastases in the first case (Case 1) is not unlike that observed by Seabold, et al. in their investigation of other non-mineralocorticoid-secreting adrenocortical carcinomas (22). Imaging of the metastatic deposits may have been possible as a result of the resection of the primary tumor. However, the remaining contralat- eral adrenal cortex did not appear to interfere with the accumulation of NP-59 into the metastases and sug- gésts that the primary lesion should have imaged. Not unlike the case reported by Greathouse et al. a carci- noma was not suspected preoperatively in Case 2 (25). The biochemistry and results of imaging, both by CT and especially scintigraphy, suggested a classic but unusually large adrenal adenoma. The size of the tum- or in case 3, its effects upon surrounding tissues and biochemistry (elevated 17 KS levels), all suggested its potential for being a malignancy, and the postoperative pathological results came as no surprise. The pres- ence of adrenocortical NP-59 uptake may be useful as both cases 2 and 3 manifested suspicious DOC levels postoperatively, and thus follow-up NP-59 scintigraphy may be useful in later clinical evaluations of these patients.
ACKNOWLEDGMENTS
We wish to thank Dr. T. Mangner and H. Anderson-Davis for the synthesis of 131-1-NP-59, the Phoenix Memorial Laboratories for the use of their radio-chemical facilities and Ms. J. Boldt for preparation of this manuscript.
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