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Computed tomographic scanning versus radioisotope imaging in adrenocortical diagnosis
Computed Tomographic Scanning versus Radioisotope Imaging in Adrenocortical Diagnosis
CHRIS K. GUERIN, M.D. HEINZ W. WAHNER, M.D. COLUM A. GORMAN, M.D. PAUL C. CARPENTER, M.D. PATRICK F. SHEEDY II, M.D. Rochester, Minnesota
Referral patterns from internists to departments of nuclear medicine or radiology are important determinants of whether adrenal glands are imaged by computed tomography (CT) or by radioisotope scintigraphy. To assist clinicians in making an informed choice, computed tomographic scans were compared with isotope scintigrams using 1311-19-iodocholesterol (194C) and 1311-6fl-iodomethyl-IO-norcholesterol (NP-59). In general, imaging techniques serve to localize diseases that are diagnosed on the basis of biochemical tests of adrenal function. Computed tomographic scanning and NP-59 scanning are of comparable diagnostic accuracy. Both are superior to 19-IC scanning in the diagnosis of Cushing’s syndrome and primary aldosteronism. Computed tomographic scanning is faster and less expensive, and involves lower radiation doses to the patient than scintigraphy. Adrenocortical isotope scanning as a routine procedure has been superseded by computed tomographic scanning at the Mayo Clinic. In the diagnostic evaluation of patients with adrenal disorders, rapidly advancing knowledge has often resulted in newer techniques that quickly supersede previously useful diagnostic tests. Among biochemical tests, measurements of urinary 17-ketosteroids and ketogenie steroids have largely been supplanted by specific measurements of cortisol and androgens or their metabolites. At present, biochemical tests of adrenal function are primarily used to define the type of adrenal disease. Adrenal imaging techniques are then employed to localize the pathologic process either to one or both adrenal glands or to ectopic adrenal tissue. Techniques for adrenal imaging also have evolved rapidly. To help define the relative merits of adrenal imaging with 19-norcho1311-19-iodocholesterol (19-IC) and 13’ IS@iodomethyllesterol (NP-59), and computed tomography, we examined each diagnostic technique in regard to diagnostic reliability, radiation dosage, and cost to the patient.
From the Section of Diagnostic Nuclear Medicine, the Division of Endocrinoloctv. Metabolism and Internal Medicine, and the Department of Diagnostic Radiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Requests for reprints should be addressed to Dr. Colum A. Gorman, Division of Endocrinology, Metabolism and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. Manuscript acceptad March 3, 1983.
PATIENTS AND METHODS One hundred patients who underwent adrenal scintigraphy at our institution between 1973 and 1981 and who had tissue confirmation of the final diagnosis or primary aldosteronism due to hyperplasia were included in the study. There were 43 men and 57 women, with ages that averaged 49 years and ranged from 19 to 75 years. Adrenal scanning or scintigraphy was performed with 19-IC since 1973 and with NP-59 later. Forty-eight patients studied after 1976 also had computed tomographic scanning of the adrenal region.
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TABLE I
Diagnostic Accuracy in Patients with Adrenal Disorders Number of
Disorder Cushing’s syndrome Primary aldosteronism Nonfunctional tumors
Patients’ 28 58 13
’
Percenlage of Patientst ‘3’1-19 NP-59 86 64 67
93 88 100
CT 90 91 89
l One patient had a virilizing ovarian tumor. + Percentage of the total population for which the test was correct in predictingthe final pathologicdisorder.
Ail patients had biochemical evaluation prior to scintigraphy. The diagnosis of Cushing’s syndrome (28 patients) was established by the classic “low-dose” dexamethasone suppression test, in which 8 A.M. and 4 P.M. corticosteroid plasma levels and 24-hour urinary ketogenic steroid or urinary free cortisoi excretion (or both) failed to decrease by less than 50 percent on the second day of dexamethasone use (0.5 mg taken orally every six hours). Cushing’s disease was presumed to be present if these test values were suppressed to less than 50 percent of baseline on the second day of dexamethasone use (2.0 mg taken orally every six hours) and if steroid values increased significantly over baseline after metyrapone administration. If suppression was not significant, either an adrenal tumor or ectopic production of corticotropin was presumed to be present. These entities were differentiated on the basis of plasma corticotropin levels, when available. Adrenal carcinoma was considered to be more likely than a benign tumor when the levels of 17-ketosteroids and ketogenic steroids were greatly elevated. In 58 patients, primary hyperaidosteronism was diagnosed on the basis of the failure of elevated plasma or urinary aidosterone (or both) to be suppressed normally with volume expansion and the failure of suppressed plasma renin to be stimulated to greater than twice baseline with volume depletion and the assumption of the upright posture. One patient had a viriiizing ovarian tumor. The remaining 13 patients had tumors that failed to secrete excess quantities of measured hormones (nonfunctional tumors). The following were indications for adrenal scintigraphy: (1) to localize an adrenal adenoma or carcinoma in the patients with clinical and biochemical evidence of Cushing’s syndrome; (2) to establish the presence of bilateral hyperplasia or ectopic adrenal tissue in the patients with Cushing’s disease; (3) to localize an adenoma and to aid in the differential diagnosis between hyperpiasia and adenoma in the patients with clinical and biochemical evidence of primary hyperaldosteronism; and (4) to localize a suspected viriiizing ovarian tumor in one patient. Adrenocorticai scintigraphy was performed as previously described and as developed by Beierwaites and associates [l]. Prior to January 1977, 19-IC was used; later, NP-59 became available. Adrenal scintigrams were interpreted as showing no adrenal uptake, unilateral uptake, or bilateral symmetric or asymmetric uptake. One patient showed ovarian uptake. lodochoiesterol obtained from the Phoenix Memorial Laboratory of the University of Michigan, Ann Arbor, was
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given intravenouslyover two to five minutes, usually at a dose of 1.5 to 2.0 mCi. Thyroid uptake was blocked with 15 drops of Lugol’s solution per day, the dose being started one day before the study and continued for two weeks. Scintigraphy was performed repeatedly for four to 17 days after 19-IC administration, and diagnostic information was generally obtainable at eight days. For NP-59, the range was one to seven days, but the diagnosis usually was evident by three days. In all patients with primary hyperaldosteronism, dexamethasone suppression (4 mg per day) was used, one to two days before and throughout the study. Patients with hypercortisolism and patients with normal biochemical results were not given dexamethasone prior to scintigraphy. Scintigraphy was performed with a tomographic scanner (Pho-Con, Searle Radiographics) and was followed by a scintigram made with a gamma camera (Pho-Gamma, Searle Radiographics). Gamma camera images were enhanced by the use of computer programs that allow subtraction of background, nine-point smoothing, and subtraction of the kidney image obtained with technetium diethylenetriaminepentaacetic acid (ggmTc-DTPA). Scan interpretations were formulated with knowledge of the clinical data. An adrenal adenoma was suspected when unilateral or asymmetric uptake was present. Adrenal hyperplasia was suspected by demonstration of bilateral symmetric uptake in the presence of biochemical evidence of adrenal hyperfunction. Patients with functional adrenocortical carcinomas usually demonstrated either bilateral nonvisualization or only contralateral visualization, often in the presence of roentgenographic evidence of a large mass. Computed tomographic scanning has been performed with state-of-the-art instruments since 1976. Adrenal tumors were directly visualized by computed tomographic scanning. Adrenal hyperpiasia was inferred when bilateral adrenal enlargement was present or when the adrenal glands were without distinct masses in the appropriate biochemical setting. Technical capability and resolution have progressively improved. Current practice during computed tomographic scanning of adrenocorticai lesions involves using several current-generation computed tomographic units (including EMI 7070, Picker International 600 and 1200, and GE 9800 scanners) with 0.5 cm slices. In most cases, use of contrast medium was not required. Diagnostic accuracy or correct localization as used in this study refers to the fraction of the total population for which the test was correct in predicting the final pathologic disorder. RESULTS The diagnostic accuracy of the localization procedures is listed in Table I. in the 28 patients with Cushing’s syndrome, the baseline urinary free cortisol excretion was 5 11 f 3 17 pg per 24 hours (normal 20 to 108) and was suppressed only to 308 f 276 after dexamethasone use, 2 mg orally per day. In all eight patients with Cushing’s syndrome and an adrenal adenoma, the tumor was correctly localized by adrenal scintigraphy; for four of these patients who also underwent computed tomographic scanning, the tumor was correctly localized.
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In the 15 patients with hyperplasia, localization was correct by 19-IC scanning in four of six patients and by NP-59 scan in eight of nine patients. In the three cases with incorrect diagnosis, there was no uptake in the adrenal tissue, which was found to be hyperplastic at surgery. Review of these three cases did not illuminate the cause of the errors. One of the five patients who underwent computed tomographic scanning was considered to have a 1 cm left adrenal tumor preoperatively, but pathologic examination revealed that both adrenal glands were hyperplastic. In all five patients with adrenal carcinoma, the lesion was correctly localized, although only one underwent computed tomographic evaluation. In the 58 patients with primary aldosteronism, the baseline plasma and urine aldosterone levels were elevated at 38.7 f 19.6 ng/dl (normal 1 to 21) and 24.2 f 14.1 yg per day (normal 4 to 16), respectively, and the upright plasma renin was suppressed to 0.74 f 0.71 ng/ml per hour. An aldosterone-producing adenoma was correctly localized on 19-IC scanning in seven of nine cases and on NP-59 scanning in 15 of 18 cases. In the five cases with incorrect diagnosis, one scan revealed normal uptake, three showed hyperplasia, and one showed lateralization of an adenoma to the side opposite that in which the lesion was found. In three of these five cases, computed tomographic scanning was also performed, leading to the correct diagnosis of a left adrenal lesion in two. In the 14 cases in which computed tomographic scanning was carried out and an adenoma was later proved to be present, the results were incorrect in two. One scan was considered normal and one revealed bilateral adrenal enlargement. In one patient, both NP-59 and computed tomographic scanning incorrectly predicted idiopathic hyperaldosteronism, although biochemical data suggested the presence of an aldosterone-producing adenoma, which was subsequently discovered at surgery. Review of these cases in detail did not illuminate a reason for the errors, except in one case in which a “loop of bowel” was considered to be present in the left upper quadrant; in retrospect, this was probably the adenoma that was discovered at surgery. Thirty patients were presumed to have idiopathic hyperaldosteronism due to adrenal hyperplasia, and 28 of the 30 were treated medically. In this group of patients, diagnostic accuracy refers to the fraction of the total population for which the tests predicted idiopathic hyperaldosteronism. Of the four patients undergoing 19-K scanning, three had normal results. Of the 26 NP-59 scans, 24 predicted idiopathic hyperaldosteronism, one was normal, and one was suggestive of a right adrenal carcinoma. Review of the two cases revealed that the misinterpretations might have been due to a low dose of the radiopharmaceutical in one case and inter-observer disagreement in the other.
ET AL
Computed tomographic scanning was diagnostically accurate in 17 of 18 cases of idiopathic hyperaldosteronism; the possibility of a left adrenal mass was raised in one case. Follow-up one year later revealed that the patient was doing well with spironolactone therapy. One patient had an aldosterone-producing carcinoma that was suspected from biochemical data and 19-IC scanning and subsequently confirmed at surgery. Thirteen patients had tumors considered to be nonfunctioning on the basis of biochemical tests. Adenomas were correctly localized by evidence of augmented isotope uptake and increased size of the gland in five of eight and three of three patients who underwent 19-IC and NP-59 scanning, respectively. In the three patients with adenomas who had an incorrect diagnosis on 19-IC scanning, scan patterns were consistent with patterns representing normal uptake in one, hyperplastic uptake in another, and carcinomatous uptake in the third. The one patient who was considered to have carcinoma had no radioisotope uptake ipsilaterally and only slight uptake contralaterally. Three of four patients with adenomas who underwent computed tomographic scanning had correct localization. In the one computed tomographic scan that was reported to be negative a 3 cm low-density lesion was described but was considered to be a cyst. Of the two patients with nonfunctioning carcinoma, each had adrenal scintigraphy, and one underwent computed tomographic scanning that correctly localized the lesion. The patient with a virilizing ovarian tumor also had correct localization on NP-59 scanning. Computed tomographic scanning correctly showed normal adrenal glands but did not localize the left ovarian tumor. (The pelvis area was not included in the area examined.) In four institutions (two university-affiliated and two large group practices) that have both adrenal scintigraphy and computed tomographic modalities available, a survey was undertaken to compare the cost to the patient. In three of the four institutions, computed tomographic scanning was less expensive than adrenal scintigraphy. In the other institution, adrenal scintigraphy was less expensive by approximately 30 percent. Overall, the ratio of costs for computed tomographic scanning to costs for adrenal scintigraphy was 1:1.3. In our institution, adrenal venous sampling is 2.7 times more expensive than computed tomographic scanning and adrenal venography is four times more expensive. COMMENTS Adrenal scintigraphy is based on the uptake of a radiopharmaceutical by the normal or abnormal adrenal gland. Computed tomographic scanning is based on density measurements that reveal size and shape of the adrenal glands. It appears that for the adrenal diseases
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ET A:
of diagnostic interest, the uptake function is reliably increased only when size or configuration of the adrenal glands is altered to the point that this is recognizable on computed tomographic scanning. Thus, the information derived from each procedure is similar for the purpose of clinical diagnosis. Attempts to quantitate adrenal uptake or to measure uptake rates as part of scintigraphy have met with limited success. The results have not reliably contributed new information to adrenal diagnosis, and we have elected not to pursue this field of investigation further. Radionuclide scintigraphy was first utilized for evaluation of adrenocortical disorders in the early 1970s by Beierwaltes et al [I]. Early studies utilized 13’119-iodocholesterol, and subsequent advances have included development of i311-6&iodomethyl-19-norcholesterol (NP-59) and suppression scanning. NP-59 has further improved the diagnostic accuracy and decreased the interval required for diagnostic imaging [2]. Adrenal suppression scans using dexamethasone were developed to enhance the differences between the normal and the abnormal adrenal cortex [3-51. Combined with knowledge of the patient’s hormonal status, scintigraphic patterns have accurately predicted pathologic findings in approximately 90 percent in many series of patients with Cushing’s syndrome LS-lo] and primary aldosteronism [6-g]. This contrasts with a recent review by Weinberger et al [ 111, in which an aldosterone-producing adenoma was correctly localized in only 47 percent of 28 patients. Previously, nonfunctional adrenocortical tumors were reported to be seen on radioisotope scanning in small numbers of patients
1121. As noninvasive procedures, scintigraphy and computed tomographic scanning have certain advantages over other diagnostic modalities such as adrenal venography, arteriography, and adrenal venous sampling. Adrenal venography can cause rupture of intra-adrenal capillaries, resulting in hemorrhage, painful extravasation, and occasionally adrenal failure [ 13,141. Arteriography is less sensitive than venography [ 151. Adrenal venous sampling, performed with or without adrenal venography, can be technically difficult, and traumatic complications may occur, as with adrenal venography. Scintigraphy might be preferred to computed tomographic scanning when contrast material is needed in computed tomography, since about 5 percent of patients are allergic to radiographic contrast media. In only 20 percent of our patients was contrast material used for computed tomographic scanning, and there was no significant difference in diagnostic accuracy between the group that received contrast medium and the group that did not. One of the main disadvantages to adrenal scintigra-
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phy has been the length of time needed to complete the scanning. The procedure may require as long as 10 days with 19-IC [6,8,10] and seven days with NP-59 [2,7,8], in addition to the one to two days needed if a suppression scan is being performed. Lack of availability of NP-59 for routine use has been proposed as a drawback [ 161, althoug;l NP-59 is available upon request despite its status as an investigational drug. In addition to being more convenient [ 171, for most medical centers computed tomographic scanning is less costly than scintigraphy. In the survey of four institutions, scintigraphy was approximately 1.3 times more expensive than computed tomographic scanning. Adrenal venous sampling and adrenal venography were 2.7 and 4.0 times more costly than computed tomography, respectively. In addition, both are invasive procedures. With scintigraphy, the dose of radiation exposure to human adrenal glands has been estimated to average between 25 and 57 rads/mCi [8,16], although the range was 12 to 160 in one study [ 181. Gross et al [ 191 have reported that, with dexamethasone suppression, an approximate reduction of 50 percent in adrenal uptake occurs, which should result in a proportionate decrease in absorbed radiation dose. With computed tomographic scanning, the average radiation exposure to human adrenal glands was approximately 2.8 rads per study with a range of 2 to 10 [20]. Therefore, scintigraphy involves five to 10 times more adrenal radiation than computed tomographic scanning. As pointed out by Schambelan et al [ 161, the clinical significance of this higher radiation dose is unknown, especially if adrenal extirpation is performed. It is not generally appreciated that radiation dose to the gonad from adrenal scanning is approximately 4 to 8 rads/mCi with 19-IC and NP-59 [8,21]. These gonadal doses are in the range encountered during 13’1therapy of Graves’ disease. The dose to the gonads from computed tomographic scanning of the adrenals is, by comparison, negligible. The results of computed tomographic scanning are more impressive when one considers that this study includes results obtained with early computed tomographic scanning equipment. Moreover, during the study period, additional patients with adrenal disease had computed tomographic examination only and did not have comparative radionuclide scans. The resolution of computed tomographic scanners has progressively improved since their introduction into widespread clinical practice. If the current generation or future generations of computed tomographic scanners would have been available throughout this study, the overall diagnostic accuracy of computed tomographic scanning would likely have been further enhanced. In conclusion, the overall diagnostic accuracy of both NP-59 scintigraphy and computed tomographic scan-
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ning in adrenocortical lesions is approximately 90 percent. This is clearly superior to the results obtained with 1311-19-iodocholesterol on imaging equipment used prior to 1976. Computed tomographic scanning can accurately predict adrenocortical lesions even without the use of contrast material, an important point for patients known to be allergic to contrast material. Isotope scans can image adrenal hyperplasia directly, in distinction to computed tomographic scanning, but both procedures rely on clinical and biochemical data to enhance diagnostic accuracy. Computed tomographic scanning of the adrenal gland is faster and more convenient, involves lower radiation dose, and is less costly than scintigraphy. However, computed tomography may be unsuccessful if a tumor is in an ectopic location and
1.
2. 3.
4.
5.
6. 7.
8.
9.
10.
11.
Beierwaltes WH, Lieberman LM, Ansari AN, Nishiyama H: Visualization of human adrenal glands in vivo by scintillation scanning. JAMA 1971; 216: 275-277. Thrall JH, Freitas JE, Beierwaltes WH: Adrenal scintigraphy. Semin Nucl Med 1978; 8: 23-41. Gross MD, Freitas JE, Thrall JH, Grekin RJ, Beierwaltes WH: Adrenal scintiscanning and aldosteronism (letter to the editor). Ann Intern Med 1979; 91: 651-652. Gross MD, Freitas JE, Swanson DP, Brady T. Beierwaltes WH: The normal dexamethasone-suppression adrenal scintiscan J Nucl Med 1979; 20: 1131-l 135. Seabold JE, Cohen EL, Beierwaltes WH, et al: Adrenal imaging with ‘311-19-iodocholesterol in the diagnostic evaluation of patients with aldosteronism. J Clin Endocrinol Metab 1976; 42: 41-51. Troncone L: Radioiodocholesterol scintigraphy in adrenal gland tumors. Eur J Nucl Med 1980; 5: 345-356. Miles JM, Wahner HW, Carpenter PC, Salassa RM, Northcutt RC: Adrenal scintiscanning with NP-59, a new radioiodinated cholesterol agent. Mayo Clin Proc 1979; 54: 321327. Ryo UY, Johnston AS, Kim I, Pinsky SM: Adrenal scanning and uptake with 13il-6/%odomethyl-nor-cholesterol. Radiology 1978; 128: 157-161. Wahner HW, Northcutt RC, Salassa RM: Adrenal scanning: usefulness in adrenal hyperfunction. Clin Nucl Med 1977; 2: 253-264. Moses DC, Schteingart DE, Sturman MF, Beierwaltes WH, Ice RD: Efficacy of radiocholesterol imaging of the adrenal glands in Cushing’s syndrome. Surg Gynecol Obstet 1974; 139: 201-204. Weinberger MH, Grim CE, Hollifield JW, et al: Primary aldosteronism: diagnosis, localization, and treatment. Ann Intern
that area is not included on the computed tomographic scan. Scintigraphy also may have a slight advantage over tomography in the postoperative patient in whom computed tomographic findings may be obscured by artifacts from metallic clips or adhesions. For these reasons, we have essentially abandoned adrenal scintigraphy at our institution as a routine approach to localization of adrenal disease, and we rely on computed tomographic scanning for localization. NP-59, however, is available for the special case in which ectopic adrenal tissue is suspected. ACKNOWLEDGMENT We wish to acknowledge the secretarial assistance of Ms. Maree A. Kelly.
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13. 14.
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16.
17.
18.
19.
20. 21.
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Med 1979; 90: 386-395. Rizza RA, Wahner HW, Spelsberg TC, Northcutt RC, Moses HL: Visualization of nonfunctioning adrenal adenomas with iodocholesterol: possible relationship to subcellular distribution of tracer. J Nucl Med 1978; 19: 458-463. Melby JC: Identifying the adrenal lesion in primary aldosteronism (editorial). Ann Intern Med 1972; 76: 1039-1041. Conn JW, Cohen EL: Versatility of adrenal photoscanning: diagnosis of unilateral adrenal failure. Arch Intern Med 1973; 131: 554-557. Kahn PC, Kelleher MD, Egdahl RH, Melby JC: Adrenal arteriography and venography in primary aldosteronism. Radiology 1971; 101: 71-78. Schambelan M, Moss AA, Biglieri EG, White EA. Korobkin M, Rost CR: Computed tomography to determine the cause of primary aldosteronism (letter to the editor). N Engl J Med 1981; 304: 1047. Curtis JA, Brennan RE, Kurtz AB: Evaluation of adrenal disease by computed tomography. Comput Tomogr 1980; 4: 165-168. Carey JE, Thrall JH, Freitas JE, Beierwaltes WH: Absorbed dose to the human adrenals from iodomethyl-norcholesterol (l-131) “NP-59” (concise communication). J Nucl Med 1979; 20: 60-62. Gross MD, Freitas JE, Grekin RJ, Beierwaltes WH: Computed tomography to determine the cause of primary aldosteronism (letter to the editor). N Engl J Med 1981; 304: 1046. McCullough EC, Payne JT: Patient dosage in computed tomography. Radiology 1978; 129: 457-463. Beierwaltes WH, Wieland DM, Yu T. Swanson DP, Mosley ST: Adrenal imaging agents: rationale, synthesis, formulation and metabolism. Semin Nucl Med 1978; 8: 5-21.
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CHRIS K. GUERIN, M.D. HEINZ W. WAHNER, M.D. COLUM A. GORMAN, M.D. PAUL C. CARPENTER, M.D. PATRICK F. SHEEDY II, M.D. Rochester, Minnesota
Referral patterns from internists to departments of nuclear medicine or radiology are important determinants of whether adrenal glands are imaged by computed tomography (CT) or by radioisotope scintigraphy. To assist clinicians in making an informed choice, computed tomographic scans were compared with isotope scintigrams using 1311-19-iodocholesterol (194C) and 1311-6fl-iodomethyl-IO-norcholesterol (NP-59). In general, imaging techniques serve to localize diseases that are diagnosed on the basis of biochemical tests of adrenal function. Computed tomographic scanning and NP-59 scanning are of comparable diagnostic accuracy. Both are superior to 19-IC scanning in the diagnosis of Cushing’s syndrome and primary aldosteronism. Computed tomographic scanning is faster and less expensive, and involves lower radiation doses to the patient than scintigraphy. Adrenocortical isotope scanning as a routine procedure has been superseded by computed tomographic scanning at the Mayo Clinic. In the diagnostic evaluation of patients with adrenal disorders, rapidly advancing knowledge has often resulted in newer techniques that quickly supersede previously useful diagnostic tests. Among biochemical tests, measurements of urinary 17-ketosteroids and ketogenie steroids have largely been supplanted by specific measurements of cortisol and androgens or their metabolites. At present, biochemical tests of adrenal function are primarily used to define the type of adrenal disease. Adrenal imaging techniques are then employed to localize the pathologic process either to one or both adrenal glands or to ectopic adrenal tissue. Techniques for adrenal imaging also have evolved rapidly. To help define the relative merits of adrenal imaging with 19-norcho1311-19-iodocholesterol (19-IC) and 13’ IS@iodomethyllesterol (NP-59), and computed tomography, we examined each diagnostic technique in regard to diagnostic reliability, radiation dosage, and cost to the patient.
From the Section of Diagnostic Nuclear Medicine, the Division of Endocrinoloctv. Metabolism and Internal Medicine, and the Department of Diagnostic Radiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Requests for reprints should be addressed to Dr. Colum A. Gorman, Division of Endocrinology, Metabolism and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. Manuscript acceptad March 3, 1983.
PATIENTS AND METHODS One hundred patients who underwent adrenal scintigraphy at our institution between 1973 and 1981 and who had tissue confirmation of the final diagnosis or primary aldosteronism due to hyperplasia were included in the study. There were 43 men and 57 women, with ages that averaged 49 years and ranged from 19 to 75 years. Adrenal scanning or scintigraphy was performed with 19-IC since 1973 and with NP-59 later. Forty-eight patients studied after 1976 also had computed tomographic scanning of the adrenal region.
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TABLE I
Diagnostic Accuracy in Patients with Adrenal Disorders Number of
Disorder Cushing’s syndrome Primary aldosteronism Nonfunctional tumors
Patients’ 28 58 13
’
Percenlage of Patientst ‘3’1-19 NP-59 86 64 67
93 88 100
CT 90 91 89
l One patient had a virilizing ovarian tumor. + Percentage of the total population for which the test was correct in predictingthe final pathologicdisorder.
Ail patients had biochemical evaluation prior to scintigraphy. The diagnosis of Cushing’s syndrome (28 patients) was established by the classic “low-dose” dexamethasone suppression test, in which 8 A.M. and 4 P.M. corticosteroid plasma levels and 24-hour urinary ketogenic steroid or urinary free cortisoi excretion (or both) failed to decrease by less than 50 percent on the second day of dexamethasone use (0.5 mg taken orally every six hours). Cushing’s disease was presumed to be present if these test values were suppressed to less than 50 percent of baseline on the second day of dexamethasone use (2.0 mg taken orally every six hours) and if steroid values increased significantly over baseline after metyrapone administration. If suppression was not significant, either an adrenal tumor or ectopic production of corticotropin was presumed to be present. These entities were differentiated on the basis of plasma corticotropin levels, when available. Adrenal carcinoma was considered to be more likely than a benign tumor when the levels of 17-ketosteroids and ketogenic steroids were greatly elevated. In 58 patients, primary hyperaidosteronism was diagnosed on the basis of the failure of elevated plasma or urinary aidosterone (or both) to be suppressed normally with volume expansion and the failure of suppressed plasma renin to be stimulated to greater than twice baseline with volume depletion and the assumption of the upright posture. One patient had a viriiizing ovarian tumor. The remaining 13 patients had tumors that failed to secrete excess quantities of measured hormones (nonfunctional tumors). The following were indications for adrenal scintigraphy: (1) to localize an adrenal adenoma or carcinoma in the patients with clinical and biochemical evidence of Cushing’s syndrome; (2) to establish the presence of bilateral hyperplasia or ectopic adrenal tissue in the patients with Cushing’s disease; (3) to localize an adenoma and to aid in the differential diagnosis between hyperpiasia and adenoma in the patients with clinical and biochemical evidence of primary hyperaldosteronism; and (4) to localize a suspected viriiizing ovarian tumor in one patient. Adrenocorticai scintigraphy was performed as previously described and as developed by Beierwaites and associates [l]. Prior to January 1977, 19-IC was used; later, NP-59 became available. Adrenal scintigrams were interpreted as showing no adrenal uptake, unilateral uptake, or bilateral symmetric or asymmetric uptake. One patient showed ovarian uptake. lodochoiesterol obtained from the Phoenix Memorial Laboratory of the University of Michigan, Ann Arbor, was
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given intravenouslyover two to five minutes, usually at a dose of 1.5 to 2.0 mCi. Thyroid uptake was blocked with 15 drops of Lugol’s solution per day, the dose being started one day before the study and continued for two weeks. Scintigraphy was performed repeatedly for four to 17 days after 19-IC administration, and diagnostic information was generally obtainable at eight days. For NP-59, the range was one to seven days, but the diagnosis usually was evident by three days. In all patients with primary hyperaldosteronism, dexamethasone suppression (4 mg per day) was used, one to two days before and throughout the study. Patients with hypercortisolism and patients with normal biochemical results were not given dexamethasone prior to scintigraphy. Scintigraphy was performed with a tomographic scanner (Pho-Con, Searle Radiographics) and was followed by a scintigram made with a gamma camera (Pho-Gamma, Searle Radiographics). Gamma camera images were enhanced by the use of computer programs that allow subtraction of background, nine-point smoothing, and subtraction of the kidney image obtained with technetium diethylenetriaminepentaacetic acid (ggmTc-DTPA). Scan interpretations were formulated with knowledge of the clinical data. An adrenal adenoma was suspected when unilateral or asymmetric uptake was present. Adrenal hyperplasia was suspected by demonstration of bilateral symmetric uptake in the presence of biochemical evidence of adrenal hyperfunction. Patients with functional adrenocortical carcinomas usually demonstrated either bilateral nonvisualization or only contralateral visualization, often in the presence of roentgenographic evidence of a large mass. Computed tomographic scanning has been performed with state-of-the-art instruments since 1976. Adrenal tumors were directly visualized by computed tomographic scanning. Adrenal hyperpiasia was inferred when bilateral adrenal enlargement was present or when the adrenal glands were without distinct masses in the appropriate biochemical setting. Technical capability and resolution have progressively improved. Current practice during computed tomographic scanning of adrenocorticai lesions involves using several current-generation computed tomographic units (including EMI 7070, Picker International 600 and 1200, and GE 9800 scanners) with 0.5 cm slices. In most cases, use of contrast medium was not required. Diagnostic accuracy or correct localization as used in this study refers to the fraction of the total population for which the test was correct in predicting the final pathologic disorder. RESULTS The diagnostic accuracy of the localization procedures is listed in Table I. in the 28 patients with Cushing’s syndrome, the baseline urinary free cortisol excretion was 5 11 f 3 17 pg per 24 hours (normal 20 to 108) and was suppressed only to 308 f 276 after dexamethasone use, 2 mg orally per day. In all eight patients with Cushing’s syndrome and an adrenal adenoma, the tumor was correctly localized by adrenal scintigraphy; for four of these patients who also underwent computed tomographic scanning, the tumor was correctly localized.
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In the 15 patients with hyperplasia, localization was correct by 19-IC scanning in four of six patients and by NP-59 scan in eight of nine patients. In the three cases with incorrect diagnosis, there was no uptake in the adrenal tissue, which was found to be hyperplastic at surgery. Review of these three cases did not illuminate the cause of the errors. One of the five patients who underwent computed tomographic scanning was considered to have a 1 cm left adrenal tumor preoperatively, but pathologic examination revealed that both adrenal glands were hyperplastic. In all five patients with adrenal carcinoma, the lesion was correctly localized, although only one underwent computed tomographic evaluation. In the 58 patients with primary aldosteronism, the baseline plasma and urine aldosterone levels were elevated at 38.7 f 19.6 ng/dl (normal 1 to 21) and 24.2 f 14.1 yg per day (normal 4 to 16), respectively, and the upright plasma renin was suppressed to 0.74 f 0.71 ng/ml per hour. An aldosterone-producing adenoma was correctly localized on 19-IC scanning in seven of nine cases and on NP-59 scanning in 15 of 18 cases. In the five cases with incorrect diagnosis, one scan revealed normal uptake, three showed hyperplasia, and one showed lateralization of an adenoma to the side opposite that in which the lesion was found. In three of these five cases, computed tomographic scanning was also performed, leading to the correct diagnosis of a left adrenal lesion in two. In the 14 cases in which computed tomographic scanning was carried out and an adenoma was later proved to be present, the results were incorrect in two. One scan was considered normal and one revealed bilateral adrenal enlargement. In one patient, both NP-59 and computed tomographic scanning incorrectly predicted idiopathic hyperaldosteronism, although biochemical data suggested the presence of an aldosterone-producing adenoma, which was subsequently discovered at surgery. Review of these cases in detail did not illuminate a reason for the errors, except in one case in which a “loop of bowel” was considered to be present in the left upper quadrant; in retrospect, this was probably the adenoma that was discovered at surgery. Thirty patients were presumed to have idiopathic hyperaldosteronism due to adrenal hyperplasia, and 28 of the 30 were treated medically. In this group of patients, diagnostic accuracy refers to the fraction of the total population for which the tests predicted idiopathic hyperaldosteronism. Of the four patients undergoing 19-K scanning, three had normal results. Of the 26 NP-59 scans, 24 predicted idiopathic hyperaldosteronism, one was normal, and one was suggestive of a right adrenal carcinoma. Review of the two cases revealed that the misinterpretations might have been due to a low dose of the radiopharmaceutical in one case and inter-observer disagreement in the other.
ET AL
Computed tomographic scanning was diagnostically accurate in 17 of 18 cases of idiopathic hyperaldosteronism; the possibility of a left adrenal mass was raised in one case. Follow-up one year later revealed that the patient was doing well with spironolactone therapy. One patient had an aldosterone-producing carcinoma that was suspected from biochemical data and 19-IC scanning and subsequently confirmed at surgery. Thirteen patients had tumors considered to be nonfunctioning on the basis of biochemical tests. Adenomas were correctly localized by evidence of augmented isotope uptake and increased size of the gland in five of eight and three of three patients who underwent 19-IC and NP-59 scanning, respectively. In the three patients with adenomas who had an incorrect diagnosis on 19-IC scanning, scan patterns were consistent with patterns representing normal uptake in one, hyperplastic uptake in another, and carcinomatous uptake in the third. The one patient who was considered to have carcinoma had no radioisotope uptake ipsilaterally and only slight uptake contralaterally. Three of four patients with adenomas who underwent computed tomographic scanning had correct localization. In the one computed tomographic scan that was reported to be negative a 3 cm low-density lesion was described but was considered to be a cyst. Of the two patients with nonfunctioning carcinoma, each had adrenal scintigraphy, and one underwent computed tomographic scanning that correctly localized the lesion. The patient with a virilizing ovarian tumor also had correct localization on NP-59 scanning. Computed tomographic scanning correctly showed normal adrenal glands but did not localize the left ovarian tumor. (The pelvis area was not included in the area examined.) In four institutions (two university-affiliated and two large group practices) that have both adrenal scintigraphy and computed tomographic modalities available, a survey was undertaken to compare the cost to the patient. In three of the four institutions, computed tomographic scanning was less expensive than adrenal scintigraphy. In the other institution, adrenal scintigraphy was less expensive by approximately 30 percent. Overall, the ratio of costs for computed tomographic scanning to costs for adrenal scintigraphy was 1:1.3. In our institution, adrenal venous sampling is 2.7 times more expensive than computed tomographic scanning and adrenal venography is four times more expensive. COMMENTS Adrenal scintigraphy is based on the uptake of a radiopharmaceutical by the normal or abnormal adrenal gland. Computed tomographic scanning is based on density measurements that reveal size and shape of the adrenal glands. It appears that for the adrenal diseases
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of diagnostic interest, the uptake function is reliably increased only when size or configuration of the adrenal glands is altered to the point that this is recognizable on computed tomographic scanning. Thus, the information derived from each procedure is similar for the purpose of clinical diagnosis. Attempts to quantitate adrenal uptake or to measure uptake rates as part of scintigraphy have met with limited success. The results have not reliably contributed new information to adrenal diagnosis, and we have elected not to pursue this field of investigation further. Radionuclide scintigraphy was first utilized for evaluation of adrenocortical disorders in the early 1970s by Beierwaltes et al [I]. Early studies utilized 13’119-iodocholesterol, and subsequent advances have included development of i311-6&iodomethyl-19-norcholesterol (NP-59) and suppression scanning. NP-59 has further improved the diagnostic accuracy and decreased the interval required for diagnostic imaging [2]. Adrenal suppression scans using dexamethasone were developed to enhance the differences between the normal and the abnormal adrenal cortex [3-51. Combined with knowledge of the patient’s hormonal status, scintigraphic patterns have accurately predicted pathologic findings in approximately 90 percent in many series of patients with Cushing’s syndrome LS-lo] and primary aldosteronism [6-g]. This contrasts with a recent review by Weinberger et al [ 111, in which an aldosterone-producing adenoma was correctly localized in only 47 percent of 28 patients. Previously, nonfunctional adrenocortical tumors were reported to be seen on radioisotope scanning in small numbers of patients
1121. As noninvasive procedures, scintigraphy and computed tomographic scanning have certain advantages over other diagnostic modalities such as adrenal venography, arteriography, and adrenal venous sampling. Adrenal venography can cause rupture of intra-adrenal capillaries, resulting in hemorrhage, painful extravasation, and occasionally adrenal failure [ 13,141. Arteriography is less sensitive than venography [ 151. Adrenal venous sampling, performed with or without adrenal venography, can be technically difficult, and traumatic complications may occur, as with adrenal venography. Scintigraphy might be preferred to computed tomographic scanning when contrast material is needed in computed tomography, since about 5 percent of patients are allergic to radiographic contrast media. In only 20 percent of our patients was contrast material used for computed tomographic scanning, and there was no significant difference in diagnostic accuracy between the group that received contrast medium and the group that did not. One of the main disadvantages to adrenal scintigra-
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phy has been the length of time needed to complete the scanning. The procedure may require as long as 10 days with 19-IC [6,8,10] and seven days with NP-59 [2,7,8], in addition to the one to two days needed if a suppression scan is being performed. Lack of availability of NP-59 for routine use has been proposed as a drawback [ 161, althoug;l NP-59 is available upon request despite its status as an investigational drug. In addition to being more convenient [ 171, for most medical centers computed tomographic scanning is less costly than scintigraphy. In the survey of four institutions, scintigraphy was approximately 1.3 times more expensive than computed tomographic scanning. Adrenal venous sampling and adrenal venography were 2.7 and 4.0 times more costly than computed tomography, respectively. In addition, both are invasive procedures. With scintigraphy, the dose of radiation exposure to human adrenal glands has been estimated to average between 25 and 57 rads/mCi [8,16], although the range was 12 to 160 in one study [ 181. Gross et al [ 191 have reported that, with dexamethasone suppression, an approximate reduction of 50 percent in adrenal uptake occurs, which should result in a proportionate decrease in absorbed radiation dose. With computed tomographic scanning, the average radiation exposure to human adrenal glands was approximately 2.8 rads per study with a range of 2 to 10 [20]. Therefore, scintigraphy involves five to 10 times more adrenal radiation than computed tomographic scanning. As pointed out by Schambelan et al [ 161, the clinical significance of this higher radiation dose is unknown, especially if adrenal extirpation is performed. It is not generally appreciated that radiation dose to the gonad from adrenal scanning is approximately 4 to 8 rads/mCi with 19-IC and NP-59 [8,21]. These gonadal doses are in the range encountered during 13’1therapy of Graves’ disease. The dose to the gonads from computed tomographic scanning of the adrenals is, by comparison, negligible. The results of computed tomographic scanning are more impressive when one considers that this study includes results obtained with early computed tomographic scanning equipment. Moreover, during the study period, additional patients with adrenal disease had computed tomographic examination only and did not have comparative radionuclide scans. The resolution of computed tomographic scanners has progressively improved since their introduction into widespread clinical practice. If the current generation or future generations of computed tomographic scanners would have been available throughout this study, the overall diagnostic accuracy of computed tomographic scanning would likely have been further enhanced. In conclusion, the overall diagnostic accuracy of both NP-59 scintigraphy and computed tomographic scan-
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ning in adrenocortical lesions is approximately 90 percent. This is clearly superior to the results obtained with 1311-19-iodocholesterol on imaging equipment used prior to 1976. Computed tomographic scanning can accurately predict adrenocortical lesions even without the use of contrast material, an important point for patients known to be allergic to contrast material. Isotope scans can image adrenal hyperplasia directly, in distinction to computed tomographic scanning, but both procedures rely on clinical and biochemical data to enhance diagnostic accuracy. Computed tomographic scanning of the adrenal gland is faster and more convenient, involves lower radiation dose, and is less costly than scintigraphy. However, computed tomography may be unsuccessful if a tumor is in an ectopic location and
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Beierwaltes WH, Lieberman LM, Ansari AN, Nishiyama H: Visualization of human adrenal glands in vivo by scintillation scanning. JAMA 1971; 216: 275-277. Thrall JH, Freitas JE, Beierwaltes WH: Adrenal scintigraphy. Semin Nucl Med 1978; 8: 23-41. Gross MD, Freitas JE, Thrall JH, Grekin RJ, Beierwaltes WH: Adrenal scintiscanning and aldosteronism (letter to the editor). Ann Intern Med 1979; 91: 651-652. Gross MD, Freitas JE, Swanson DP, Brady T. Beierwaltes WH: The normal dexamethasone-suppression adrenal scintiscan J Nucl Med 1979; 20: 1131-l 135. Seabold JE, Cohen EL, Beierwaltes WH, et al: Adrenal imaging with ‘311-19-iodocholesterol in the diagnostic evaluation of patients with aldosteronism. J Clin Endocrinol Metab 1976; 42: 41-51. Troncone L: Radioiodocholesterol scintigraphy in adrenal gland tumors. Eur J Nucl Med 1980; 5: 345-356. Miles JM, Wahner HW, Carpenter PC, Salassa RM, Northcutt RC: Adrenal scintiscanning with NP-59, a new radioiodinated cholesterol agent. Mayo Clin Proc 1979; 54: 321327. Ryo UY, Johnston AS, Kim I, Pinsky SM: Adrenal scanning and uptake with 13il-6/%odomethyl-nor-cholesterol. Radiology 1978; 128: 157-161. Wahner HW, Northcutt RC, Salassa RM: Adrenal scanning: usefulness in adrenal hyperfunction. Clin Nucl Med 1977; 2: 253-264. Moses DC, Schteingart DE, Sturman MF, Beierwaltes WH, Ice RD: Efficacy of radiocholesterol imaging of the adrenal glands in Cushing’s syndrome. Surg Gynecol Obstet 1974; 139: 201-204. Weinberger MH, Grim CE, Hollifield JW, et al: Primary aldosteronism: diagnosis, localization, and treatment. Ann Intern
that area is not included on the computed tomographic scan. Scintigraphy also may have a slight advantage over tomography in the postoperative patient in whom computed tomographic findings may be obscured by artifacts from metallic clips or adhesions. For these reasons, we have essentially abandoned adrenal scintigraphy at our institution as a routine approach to localization of adrenal disease, and we rely on computed tomographic scanning for localization. NP-59, however, is available for the special case in which ectopic adrenal tissue is suspected. ACKNOWLEDGMENT We wish to acknowledge the secretarial assistance of Ms. Maree A. Kelly.
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Med 1979; 90: 386-395. Rizza RA, Wahner HW, Spelsberg TC, Northcutt RC, Moses HL: Visualization of nonfunctioning adrenal adenomas with iodocholesterol: possible relationship to subcellular distribution of tracer. J Nucl Med 1978; 19: 458-463. Melby JC: Identifying the adrenal lesion in primary aldosteronism (editorial). Ann Intern Med 1972; 76: 1039-1041. Conn JW, Cohen EL: Versatility of adrenal photoscanning: diagnosis of unilateral adrenal failure. Arch Intern Med 1973; 131: 554-557. Kahn PC, Kelleher MD, Egdahl RH, Melby JC: Adrenal arteriography and venography in primary aldosteronism. Radiology 1971; 101: 71-78. Schambelan M, Moss AA, Biglieri EG, White EA. Korobkin M, Rost CR: Computed tomography to determine the cause of primary aldosteronism (letter to the editor). N Engl J Med 1981; 304: 1047. Curtis JA, Brennan RE, Kurtz AB: Evaluation of adrenal disease by computed tomography. Comput Tomogr 1980; 4: 165-168. Carey JE, Thrall JH, Freitas JE, Beierwaltes WH: Absorbed dose to the human adrenals from iodomethyl-norcholesterol (l-131) “NP-59” (concise communication). J Nucl Med 1979; 20: 60-62. Gross MD, Freitas JE, Grekin RJ, Beierwaltes WH: Computed tomography to determine the cause of primary aldosteronism (letter to the editor). N Engl J Med 1981; 304: 1046. McCullough EC, Payne JT: Patient dosage in computed tomography. Radiology 1978; 129: 457-463. Beierwaltes WH, Wieland DM, Yu T. Swanson DP, Mosley ST: Adrenal imaging agents: rationale, synthesis, formulation and metabolism. Semin Nucl Med 1978; 8: 5-21.
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