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Adrenal scintigraphy
Adrenal Scintigraphy By Rajendra Kumar, Ruppert David, Bettye A. Sayle, and Lamk M. Lamki
MAGIN G of the adrenal glands has been greatly facilitated with the advent of CT and MRL However, these modalities allow us to study only the morphologic aspects of the glands. Adrenal scintigraphy is the only noninvasive technique that provides information about both the structure and function of the glands. It has proved useful in the detection of adrenal lesions that are either too small to visualize with other means or ectopic in location. In most instances, adrenal scintigraphy is a complementary procedure, useful in localizing the abnormal adrenal tissue once the diagnosis of adrenal dysfunction has been established biochemically. Thus, it is essential that the results of scintigraphy be correlated with clinical and with biochemical and other imaging data. I ,2 Adrenal scintigraphy may be divided into adrenal cortical and adrenal medullary imaging, and different radiopharmaceuticals are used in each.
I
ADRENAL CORTICAL IMAGING
The adrenal cortex comprises 90%of the gland volume and is responsible for the production of mineralocorticoids (mainly aldrosterone) by the outer cortical layer (zona glomerulosa), glucocorticoids (mainly cortisol) by the middle layer (zona fasciculata), and adrenal androgens by the innermost layer (zona reticularis).' The growth and secretory function of the adrenal cortex are regulated by the anterior pituitary adrenocorticotropic hormone (ACTH), which in turn is under the control of the hypothalamic releasing factor. ACTH has its maximum influence on cortisol secretion, whereas aldosterone secretion is controlled by angiotensin II, plasma electrolytes, and blood volume, under the influence of the juxtaglomerular apparatus of the renal tubules. Hypersecretion of each of these hormones produces a characteristic clinical syndrome. Radioisotope Selection Cholesterol is stored in the adrenal cortex and is used as a precursor in the biosynthesis of the adrenal cortical hormones. 13I1-iodocholesterol was the first radiopharmaceutical used success-
fully in adrenal cortical imaging, in 1971.4 Subsequently, 6~-iodo-19-methyl-norcholesterol (NP-59) tagged with 131 1 was found to be a superior agent because of its greater ratio of target to background and higher adrenal uptake.' At present, it is the agent of choice for adrenal cortical imaging and is available in the United States through the Nuclear Medicine Division of the University of Michigan. Irradiation dose is acceptable for the target (adrenal) organ and varies with the size and functional status of the adrenal glands." Procedure. Two days prior to the administration of radioisotope tracer, the patient is started on 3 drops of Lugol's iodine solution twice a day, which is continued for 2 weeks to block thyroidal uptake of any free 131 1 in Np-59. Then, 2 mCi of 1311-labeled NP-59 is injected intravenously. Imaging is initiated from day 2 and performed daily for 5 to 7 days. The patient lies prone and a gamma camera with a high-energy collimator is positioned over the thoracolumbar region. The images are acquired over a period of 20 minutes, with a minimum count of 50K. Oblique and lateral scans may be obtained if necessary. Digital images are preferred to analogue because they are more amenable to computer processing for enhancing contrast and subtracting background. Normal adrenal glands usually show minimal Np·59 uptake. At times, radioactivity is seen in the liver, gallbladder, and large bowel and may interfere with interpretation of the adrenal images.' This can be overcome by giving a fatty From the Department oj Radiology, The University of Texas Medical Branch, Galveston; the Department oj Radiology, Baylor College of Medicine, Houston; and the Department of Radiology and Nuclear Medicine, University of Texas M.D. Anderson Hospital and Tumor Institute, Houston. Rajendra Kumar, Associate Professor ofRadiology; Ruppert David, Assistant Professor of Radiology; Bettye A. Sayle, Associate Professor of Radiology; Lamk M. Larnki, Associate Professor ofRadiology. Address reprint requests to Rajendra Kumar, MD, The University oj Texas Medical Branch, Department ofRadiology G-09,Galveston, TX 77550. © 1988 by Grune & Stratton, Inc. 0037-198X/88/2304-0003$5.00/0
Seminars in Roentgenology, Vol XXIII, No 4 (October), 1986: pp 243-249
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meal and a laxative to the patient, resulting in most cases in disappearance of the undesired radioactivity. The percentage of uptake of the radioactivity in each adrenal gland can be calculated using a phantom, background subtraction, and depth correction for tissue attenuation. Even though there may be overlap between normal and abnormal values with these quantitative maneuvers, an extremely high percentage of uptake of the tracer indicates adrenal gland abnormality. Normal adrenal gland uptake of the radiotracer can be totally suppressed by oral dexamethasone, as little as 2 mg per day. If the dexamethasone is abruptly discontinued, both adrenals may image normally within two days. Patient medication during dexamethasone suppression is critical; oral contraceptives, low salt diet, and diuretics may influence the results." Dexamethasone suppresses normal adrenal gland function." Excessive amounts of ACTH either from the pituitary or by ectopic secretion by various neoplasms prevent this suppression." Suppression of the normal adrenal activity by dexamethasone does not exclude adrenal hyperfunction and should be correlated with other clinical and laboratory tests in every case. Sup-
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Fig 1. Cushing's syndrome secondary to ACTH-dependent bilateral adrenal hyperplasia. Adrenal uptake on day 5 was 2% on the right and 1.6% on the left (normal uptake 0.3% or less).
pression with dexamethasone is performed mainly to distinguish between adrenal adenoma and bilateral adrenal hyperplasia in patients with hyperaldosteronism and hyperandrogenism.P'" The study can be performed in these patients directly, without prior NP-59 adrenal imaging. Hypercortisolism Pituitary-Dependent ACTH Excess (Cushing Syndrome) In most adults, Cushing syndrome is caused by bilateral adrenal hyperplasia as a result of excess production of ACTH by the pituitary. Once the diagnosis of hypercortisolism is established on clinical and biochemical grounds, the nonsuppressed adrenal scintigram will show greater than normal radioisotope uptake in both adrenal glands (Fig 1). The glands may be enlarged. In ectopic production, the plasma ACTH levels are usually markedly elevated, and bilateral adrenal uptake of the labeled NP-59 is much higher (Fig 2).12
Adrenal Cortical Adenoma Unilateral visualization of the adrenal gland containing the tumor is the result of the excess
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Fig 2. Bilateral adrenal hyperplasia due to ectopic ACTH overproduction in a patient with bronchogenic carcinoma. Adrenal uptake on day 4 was 2 % on the left and 1.5% on the right (normel 0.3% or less).
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ADRENAL SCINTIGRAPHY
cortisol production by the adenoma. This hormone reduces the ACTH and thereby suppresses the contralateral normal adrenal gland. Adrenal cortical scintigraphy may prove superior to other imaging modalities as it reveals both the location of the adrenal tumor and its hyperfunction.
Adrenal Carcinoma Adrenal carcinoma is the most common cause of Cushing syndrome in children. Adrenal cortical scintigraphy typically fails to visualize the adrenals. The radioactivity in the functioning carcinoma is decreased because of the inefficiency of the neoplastic tissue in hormone production, and the poor ratio of target to background results in nonvisualization of the tumor. The contralateral normal adrenal gland uptake is suppressed because of excessive cortisol production by the carcinoma. Patients with adrenal carcinoma treated with o,p'-DDD (Lysodren, Bristol Laboratories) can also be assessed by scintigraphy. 13 Postadrenalectomy Remnants Adrenal cortical scintigraphy is useful in patients who continue to have symptoms of hypercortisolism following adrenalectomy. I The hyperfunctioning remnant of adrenal tissue is readily localized by scintigraphy but is often missed by other imaging modalities because the lesion must attain appreciable size before it can be detected radiographically.
the aldosterone-producing lesion. Dexamethasone suppression is required for localization of the underlying cause. 10 The patient receives 4 mg dexamethasone daily for seven days before the test and during the entire imaging period. The normal adrenal cortex may be visualized five days after the administration of NP-59 while the patient is on continuous dexamethasone suppression. This "escape" phenomenon is frequently observed but poorly understood. It is critical that the images be obtained daily during the course of the study. The patient with an aldosteronoma shows a nonsuppressible uptake of the tracer by the adenoma prior to the fifth day after injection (Fig 3). Marked asymmetric radioactive uptake in the adrenal glands may be seen thereafter, as the activity of the contralateral normal adrenal is suppressed by dexamethasone.l-'? In patients with bilateral macronodular adrenal hyperplasia, the uptake in the glands is symmetrically increased both at early and at late imaging periods. In contrast, patients with bilateral micronodular adrenal hyperplasia show suppressed adrenal function with decreased uptake during the first three days and increased uptake after this period. Bilateral adrenal uptake occurring later than five days after injection is nondiagnostic. I The sensitivity and specificity of
Aldosteronism
Primary Aldosteronism (Conn Syndrome) Primary aldosteronism may occur as a result of hyperplasia or adenoma of the zona glomerulosa.' In most cases, hypokalemia, hypernatremia, low plasma renin, and hypertension occur. 14 In contrast, secondary aldosteronism results in a response to extra-adrenal stimuli and is characterized by increased plasma renin activity. It is rarely due to a primary renin-producing tumor. Because adenoma is treated surgically and bilateral hyperplasia requires conservative medical treatment, it is essential to differentiate between the two conditions. In primary aldosteronism, unsuppressed NP59 adrenal cortical scintigraphy has not proved useful because normal cortisol-producing adrenal tissue localizes the tracer and obscures
L Fig 3. Aldosteronoma. Dexamethasone-suppressed NP-59 scintigraphy shows increased uptake by the tumor in the left adrenal. Tracer is also pres ant in the descending colon (arrows). The right adrenal is not visualized.
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dexamethasone-suppressed NP-59 scintigraphy are about 90% for each and equal or exceed those for CT in detection and diagnosis of primary aldosteronism. I
Adrenal Hyperandrogenism Virilism may be caused by excessive androgen secretion by an adrenal cortical adenoma or carcinoma arising in the zona reticularis.' Since virilization may also be caused by an androgenproducing ovarian tumor, it is essential that the exact source of excessive androgen production be established prior to treatment. Dexamethonesuppressed adrenal cortical scintigraphy is helpful in such situations and can be performed in a manner similar to the study for hyperaldosteronism." The scan will show an early increased uptake (before the fifth day) by the hyperfunctioning adenoma, and no uptake will be seen in the case of androgen-secreting carcinoma. In both cases, the contralateral normal adrenal gland will show normal uptake. It is not unusual to find excessive cortisol production with androgen-producing carcinoma. In such an event, the contralateral normal adrenal gland will be suppressed by shutdown of pituitary ACTH, resulting in bilateral nonvisualization of the adrenals. Pelvic imaging may prove useful as radioiodinated NP-59 has been shown to concentrate in hyperfunctioning virilizing ovarian neoplasms. IS
Fig 4. gland.
Pheochromocytoma arising in the right adrenal
ent in the imaging of pheochromocytoma." The normal adrenal medulla is rarely visualized with 13II_MIBG scintigraphy, but pheochromocytoma is clearly seen. The radiopharmaceutical is concentrated in the heart, liver, spleen, and adrenal medulla because these organs are rich in sympathetic nerve endings.':" The radiotracer is excreted by the kidneys. Bladder activity may obscure extra-adrenal pheochromocytoma in the
ADRENAL MEDULLARY IMAGING
Pheochromocytoma Pheochromocytoma is a benign neuroectodermal neoplasm usually arising in the adrenal medulla. However, 10% of these tumors are malignant, 10% are bilateral, and 10% are extra-adrenal in location. The tumor may also be associated with neurofibromatosis, tuberous sclerosis, von Hippel-Lindau disease, and MEN syndromes. The diagnosis is made on clinical and biochemical criteria." Because the treatment requires surgical extirpation of the tumor tissue, adrenal medullary scintigraphy provides a noninvasive, specific, and sensitive method for localization of pheochromocytoma whether it is intraor extra-adrenal in origin. I Radioisotope Selection 13II-meta-iodobenzylguanidine C3II-M IBG ) is the radiopharmaceutical agent of choice at pres-
Fig 5. Ectopic pheochromocytoma in the pericardial sac. 13'I-MIBG scintiscan localizes the tumor in the mediastinum (arrow). N, neck.
ADRENAL SCINTIGRAPHY
pelvis and in the bladder, so that the imaging should be performed after the bladder is emptied. Drugs such as reserpine, phenylpropanolamine, tricyclic antidepressants , and cocaine interfere with 13II_MIBG upt ake and should be withdrawn before imaging." 123I-MIBG, which is cyclotronproduced, is much more sensitive for the detection of pheoch romocytoma, but it is expensive and not readily available. In contrast to 13lr_ MIBG, it routinely visualizes the normal adrenal medulla. 18
Fig 6. Bilateral intra-adrenal pheochromocytomas in a patient with multiple endocrine neoplasia syndrome (MEN type II). (AI 13I1-MIBG scintiscan taken 48 hours after injection shows two discrete areas of increased tracer uptake in the upper abdomen . (B) Combined 131I_MIBG and 8OmTc-DTPA scintiscan localizes the kidneys (arrows) and confirms suprarenal location of the areas of increased uptake. corresponding to the adrenals (arrowheads).
247
Procedure. 13II-MIBG is available from the University of Michigan. Three drops of Lugol's iodine solution is administrated orally to the patient twice daily to block thyroidal uptake of free radioiodine 24 hours prior to administration of the radioiodinated MIBG and is continued during the entire study. Intravenous injection of 13II_MIBG, 0.5 to 1 mCi/1.7 m 2 body surface area is given in 30 seconds . Imaging is performed with a gamma camera at 48 and 72 hours, at which time most pheochromocytomas become visible. Multiple overlapping images of the body from the skull to the bladder are taken to demonstrate extra-adrenal pheochromocytoma . Iodinated MIBG may reveal bony metastases from pheochromocytoma that are not detectable by 99mTc_M DP bone scanning." If 13II-MIBG scintigraphy reveals activity in the abdomen suggestive of pheochromocytoma, 99mTc-DT PA is injected to visualize the kidneys, thereby increasing the degree of confidence in recogniz ing the adrenal tumor. Additional imaging with 99mTc_ sulfur colloid for detection of liver metastases, and 20l-thallium for delineation of mediastinal pheochromocytoma is useful. I Clinical indications and results. Increased uptake of radioiodinated MIBG suggests the presence of a pheochromocytoma, which may be intra- or extra-adrenal in location (Figs 4 and 5). Multifocal areas of increased uptake are consistent with metastases from a primary malignant
Fig 7. MUltiple peraganglionomas (arrows) in pelvis seen on 1311_MIBG scintiscan 48 hours after injection.
KUMAR ET AL
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pheochromocytoma or multicentric primary tumor (Fig 6).18,19 Adrenal medullary imaging with 13II_MIBG provides information about the morphological and functional status of pheochromocytoma, helps to detect extra-adrenal pheochromocytoma, and assesses the extent of the disease by revealing distant metastases and multiple tumors. The technique has a sensitivity of about 85% and specificity close to 100% when pertinent clinical and biochemical data are available, as 13II-MIBG is also localized in other neuroectodermal tumors. I,18,20
Neuroblastoma and Other Tumors Besides pheochromocytoma, neuroblastoma, nonfunctioning paraganglioma (Fig 7), schwannoma, medullary thyroid carcinoma, bronchogenic carcinoma, and carcinoid tumor have also
been shown to concentrate radioiodinated MIBG, and the study may be used for localization of these tumors. I,18,20-22 More important, the study helps to distinguish neuroblastoma from Ewing sarcoma and other small round cell tumors in children since, unlike neuroblastoma, these tumors do not take up the tracer. The sensitivity of MIBG scintigraphy is about 90%, and specificity is close to 100% in the detection of neuroblastoma.P'f" TREATMENT WITH 1311_MIBG
Malignant primary and secondary pheochromocytomas have been treated with high doses (100 to 200 mCi) of radioiodinated MIBG, with varying degrees of success. 18,20,23-25 The radiopharmaceutical has also been used for staging of neuroblastoma and treatment of stage IV neuroblastoma in children.P:"
REFERENCES 1. Shapiro B, Gross MD, Sandler MP: Adrenal scintigraphy revisited: A current status report on radiotracers, clinical utility, and correlative imaging. In: Freeman LM, Weissman HS (eds): Nuclear Medicine Annual 19&7. New York: Raven 1987:193-232 2. Thrall JH, Freitas JE, Beierwaltes WH: Adrenal scintigraphy. Semin Nucl Med 1978;8:23-41 3. Nelson DH: The Adrenal Cortex: Physiological Function and Disease. Philadelphia: Saunders, 19&0:65-88 4. Blair RJ, Beierwaltes WH, Lieberman LM, et al: Radiolabeled cholesterol as an adrenal agent. J Nucl Med 1971;12:176-182 5. Sarkar SD, Cohen EL, Beierwaltes WH, et al: A new and superior adrenal imaging agent 131 1-6-iodomethyl19-norcholesterol (NP-59): Evaluation in humans. J Clin Endocrtnol Metab 1977;45:353-362 6. Carey JE, Thrall JH, Freitas JE, et al: Absorbed dose to the human adrenals from iodomethyl-norcholesterol (1-131) "NP-59." J Nucl Med 1979;20:60-62 7. Lynn MD, Gross MD, Shapiro B: Enterohepatic circulation and distribution ofI-131-6tl-iodomethyl-19-norcholesterol (NP-59). Nucl Med Comm 1986;7:625-630 8. Gross MD, Valk TW, Swanson DP, et al: The role of pharmacologic manipulation in adrenal cortical scintigraphy. Semin Nucl Med 1981;11:128-148 9. Gross MD, Freitas JE, Swanson DP, et al: The normal dexamethasone-suppression adrenal scintiscan. J Nucl Med 1979;20:1131-1135 10. Gross MD, Shapiro B, Grekin RJ, et al: Scintigraphic localization of adrenal lesions in primary aldosteronism. Am J Med 1984;77:839-844 11. Gross MD, Freitas JE, Swanson DP, et al: Dexamethasone-suppression adrenal scintigraphy in hyperandrogenism. J Nucl M ed 1981;22:12-17
12. Gold EM: The Cushing's syndromes: Changing views of diagnosis and treatment. Ann Intern Med 1979;90:829844 13. Luton JP, Mahoudeau JA, Bouchard P, et al: Treatment of Cushing's disease by o,p'DDD. N Engl J Med 1978;300:459-464 14. Conn JW: Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955;45:3-17 15. Carpenter PC, Wahner HW, Salassa RM, et al: Demonstration of steroid-producing gonadal tumors by external scanning with the use of NP-59. Mayo Clin Proc 1979;54:332-334. 16. VanHeerden JA, Sheps SG, Hamberger B, et al: Pheochromocytoma: Current status and changing trends. Surgery 1982;91:367-373 17. Francis JR, Glazer GM, Shapiro B, et al: Complementary roles of CT and 131-I-MIBG scintigraphy in diagnosing pheochromocytoma. AJR 1983;141:719-725 18. McEwan Al, Shapiro B, Sisson JC, et al: Radioiodobenzylguanidine for the scintigraphic location and therapy of adrenergic tumors. Semin Nucl Med 1985;15:132-153 19. Shapiro B, Sisson lC, Lloyd R, et al: Malignant pheochromocytoma: Clinical, biochemical and scintigraphic characterization. Clin EndocrinolI984;20:189-203 20. Hoefnagel CA, V 011te PA, deKraker 1, et al: Radionuelide diagnosis and therapy of neural crest tumors using iodine-131 metaiodo benzylguanidine. J Nucl M ed 1987;28:308-314 21. Munkner T: 131-I-metaiodobenzylguanidine scintigraphy of neuroblastomas. Semin Nucl Med 1985;15:154160 22. Feldman 1M, Blinder RA, Lucas KJ, et al: Iodine
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131-metaiodobenzylguanidine scintigraphy of carcinoid tumors . J Nucl Med 1986;27:1691-1696 23. Kimmig B, Brandeis WE, Eisenhut M, et al: Scintigraphy of a neuroblastoma with 1-131meta-iodobenzylguanidine , J Nucl Med 1984;25:773-775
24. Hattner RS, Huberty JP , Engelstad BL, et al: Localization of m-iodo 31I) benzylguanidine in neuroblastoma . AJR 1984;143:373-374 25. Podrasky AE, Stark DD, Hanner RS , et al: Rad ionuelide bone scanning in neuroblastoma: Skelet al metastases and primary tumor. AJR 1983;141:469-472
e
MAGIN G of the adrenal glands has been greatly facilitated with the advent of CT and MRL However, these modalities allow us to study only the morphologic aspects of the glands. Adrenal scintigraphy is the only noninvasive technique that provides information about both the structure and function of the glands. It has proved useful in the detection of adrenal lesions that are either too small to visualize with other means or ectopic in location. In most instances, adrenal scintigraphy is a complementary procedure, useful in localizing the abnormal adrenal tissue once the diagnosis of adrenal dysfunction has been established biochemically. Thus, it is essential that the results of scintigraphy be correlated with clinical and with biochemical and other imaging data. I ,2 Adrenal scintigraphy may be divided into adrenal cortical and adrenal medullary imaging, and different radiopharmaceuticals are used in each.
I
ADRENAL CORTICAL IMAGING
The adrenal cortex comprises 90%of the gland volume and is responsible for the production of mineralocorticoids (mainly aldrosterone) by the outer cortical layer (zona glomerulosa), glucocorticoids (mainly cortisol) by the middle layer (zona fasciculata), and adrenal androgens by the innermost layer (zona reticularis).' The growth and secretory function of the adrenal cortex are regulated by the anterior pituitary adrenocorticotropic hormone (ACTH), which in turn is under the control of the hypothalamic releasing factor. ACTH has its maximum influence on cortisol secretion, whereas aldosterone secretion is controlled by angiotensin II, plasma electrolytes, and blood volume, under the influence of the juxtaglomerular apparatus of the renal tubules. Hypersecretion of each of these hormones produces a characteristic clinical syndrome. Radioisotope Selection Cholesterol is stored in the adrenal cortex and is used as a precursor in the biosynthesis of the adrenal cortical hormones. 13I1-iodocholesterol was the first radiopharmaceutical used success-
fully in adrenal cortical imaging, in 1971.4 Subsequently, 6~-iodo-19-methyl-norcholesterol (NP-59) tagged with 131 1 was found to be a superior agent because of its greater ratio of target to background and higher adrenal uptake.' At present, it is the agent of choice for adrenal cortical imaging and is available in the United States through the Nuclear Medicine Division of the University of Michigan. Irradiation dose is acceptable for the target (adrenal) organ and varies with the size and functional status of the adrenal glands." Procedure. Two days prior to the administration of radioisotope tracer, the patient is started on 3 drops of Lugol's iodine solution twice a day, which is continued for 2 weeks to block thyroidal uptake of any free 131 1 in Np-59. Then, 2 mCi of 1311-labeled NP-59 is injected intravenously. Imaging is initiated from day 2 and performed daily for 5 to 7 days. The patient lies prone and a gamma camera with a high-energy collimator is positioned over the thoracolumbar region. The images are acquired over a period of 20 minutes, with a minimum count of 50K. Oblique and lateral scans may be obtained if necessary. Digital images are preferred to analogue because they are more amenable to computer processing for enhancing contrast and subtracting background. Normal adrenal glands usually show minimal Np·59 uptake. At times, radioactivity is seen in the liver, gallbladder, and large bowel and may interfere with interpretation of the adrenal images.' This can be overcome by giving a fatty From the Department oj Radiology, The University of Texas Medical Branch, Galveston; the Department oj Radiology, Baylor College of Medicine, Houston; and the Department of Radiology and Nuclear Medicine, University of Texas M.D. Anderson Hospital and Tumor Institute, Houston. Rajendra Kumar, Associate Professor ofRadiology; Ruppert David, Assistant Professor of Radiology; Bettye A. Sayle, Associate Professor of Radiology; Lamk M. Larnki, Associate Professor ofRadiology. Address reprint requests to Rajendra Kumar, MD, The University oj Texas Medical Branch, Department ofRadiology G-09,Galveston, TX 77550. © 1988 by Grune & Stratton, Inc. 0037-198X/88/2304-0003$5.00/0
Seminars in Roentgenology, Vol XXIII, No 4 (October), 1986: pp 243-249
243
244
KUMAR ET AL
meal and a laxative to the patient, resulting in most cases in disappearance of the undesired radioactivity. The percentage of uptake of the radioactivity in each adrenal gland can be calculated using a phantom, background subtraction, and depth correction for tissue attenuation. Even though there may be overlap between normal and abnormal values with these quantitative maneuvers, an extremely high percentage of uptake of the tracer indicates adrenal gland abnormality. Normal adrenal gland uptake of the radiotracer can be totally suppressed by oral dexamethasone, as little as 2 mg per day. If the dexamethasone is abruptly discontinued, both adrenals may image normally within two days. Patient medication during dexamethasone suppression is critical; oral contraceptives, low salt diet, and diuretics may influence the results." Dexamethasone suppresses normal adrenal gland function." Excessive amounts of ACTH either from the pituitary or by ectopic secretion by various neoplasms prevent this suppression." Suppression of the normal adrenal activity by dexamethasone does not exclude adrenal hyperfunction and should be correlated with other clinical and laboratory tests in every case. Sup-
L
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Fig 1. Cushing's syndrome secondary to ACTH-dependent bilateral adrenal hyperplasia. Adrenal uptake on day 5 was 2% on the right and 1.6% on the left (normal uptake 0.3% or less).
pression with dexamethasone is performed mainly to distinguish between adrenal adenoma and bilateral adrenal hyperplasia in patients with hyperaldosteronism and hyperandrogenism.P'" The study can be performed in these patients directly, without prior NP-59 adrenal imaging. Hypercortisolism Pituitary-Dependent ACTH Excess (Cushing Syndrome) In most adults, Cushing syndrome is caused by bilateral adrenal hyperplasia as a result of excess production of ACTH by the pituitary. Once the diagnosis of hypercortisolism is established on clinical and biochemical grounds, the nonsuppressed adrenal scintigram will show greater than normal radioisotope uptake in both adrenal glands (Fig 1). The glands may be enlarged. In ectopic production, the plasma ACTH levels are usually markedly elevated, and bilateral adrenal uptake of the labeled NP-59 is much higher (Fig 2).12
Adrenal Cortical Adenoma Unilateral visualization of the adrenal gland containing the tumor is the result of the excess
L
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Fig 2. Bilateral adrenal hyperplasia due to ectopic ACTH overproduction in a patient with bronchogenic carcinoma. Adrenal uptake on day 4 was 2 % on the left and 1.5% on the right (normel 0.3% or less).
245
ADRENAL SCINTIGRAPHY
cortisol production by the adenoma. This hormone reduces the ACTH and thereby suppresses the contralateral normal adrenal gland. Adrenal cortical scintigraphy may prove superior to other imaging modalities as it reveals both the location of the adrenal tumor and its hyperfunction.
Adrenal Carcinoma Adrenal carcinoma is the most common cause of Cushing syndrome in children. Adrenal cortical scintigraphy typically fails to visualize the adrenals. The radioactivity in the functioning carcinoma is decreased because of the inefficiency of the neoplastic tissue in hormone production, and the poor ratio of target to background results in nonvisualization of the tumor. The contralateral normal adrenal gland uptake is suppressed because of excessive cortisol production by the carcinoma. Patients with adrenal carcinoma treated with o,p'-DDD (Lysodren, Bristol Laboratories) can also be assessed by scintigraphy. 13 Postadrenalectomy Remnants Adrenal cortical scintigraphy is useful in patients who continue to have symptoms of hypercortisolism following adrenalectomy. I The hyperfunctioning remnant of adrenal tissue is readily localized by scintigraphy but is often missed by other imaging modalities because the lesion must attain appreciable size before it can be detected radiographically.
the aldosterone-producing lesion. Dexamethasone suppression is required for localization of the underlying cause. 10 The patient receives 4 mg dexamethasone daily for seven days before the test and during the entire imaging period. The normal adrenal cortex may be visualized five days after the administration of NP-59 while the patient is on continuous dexamethasone suppression. This "escape" phenomenon is frequently observed but poorly understood. It is critical that the images be obtained daily during the course of the study. The patient with an aldosteronoma shows a nonsuppressible uptake of the tracer by the adenoma prior to the fifth day after injection (Fig 3). Marked asymmetric radioactive uptake in the adrenal glands may be seen thereafter, as the activity of the contralateral normal adrenal is suppressed by dexamethasone.l-'? In patients with bilateral macronodular adrenal hyperplasia, the uptake in the glands is symmetrically increased both at early and at late imaging periods. In contrast, patients with bilateral micronodular adrenal hyperplasia show suppressed adrenal function with decreased uptake during the first three days and increased uptake after this period. Bilateral adrenal uptake occurring later than five days after injection is nondiagnostic. I The sensitivity and specificity of
Aldosteronism
Primary Aldosteronism (Conn Syndrome) Primary aldosteronism may occur as a result of hyperplasia or adenoma of the zona glomerulosa.' In most cases, hypokalemia, hypernatremia, low plasma renin, and hypertension occur. 14 In contrast, secondary aldosteronism results in a response to extra-adrenal stimuli and is characterized by increased plasma renin activity. It is rarely due to a primary renin-producing tumor. Because adenoma is treated surgically and bilateral hyperplasia requires conservative medical treatment, it is essential to differentiate between the two conditions. In primary aldosteronism, unsuppressed NP59 adrenal cortical scintigraphy has not proved useful because normal cortisol-producing adrenal tissue localizes the tracer and obscures
L Fig 3. Aldosteronoma. Dexamethasone-suppressed NP-59 scintigraphy shows increased uptake by the tumor in the left adrenal. Tracer is also pres ant in the descending colon (arrows). The right adrenal is not visualized.
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KUMAR ET AL
dexamethasone-suppressed NP-59 scintigraphy are about 90% for each and equal or exceed those for CT in detection and diagnosis of primary aldosteronism. I
Adrenal Hyperandrogenism Virilism may be caused by excessive androgen secretion by an adrenal cortical adenoma or carcinoma arising in the zona reticularis.' Since virilization may also be caused by an androgenproducing ovarian tumor, it is essential that the exact source of excessive androgen production be established prior to treatment. Dexamethonesuppressed adrenal cortical scintigraphy is helpful in such situations and can be performed in a manner similar to the study for hyperaldosteronism." The scan will show an early increased uptake (before the fifth day) by the hyperfunctioning adenoma, and no uptake will be seen in the case of androgen-secreting carcinoma. In both cases, the contralateral normal adrenal gland will show normal uptake. It is not unusual to find excessive cortisol production with androgen-producing carcinoma. In such an event, the contralateral normal adrenal gland will be suppressed by shutdown of pituitary ACTH, resulting in bilateral nonvisualization of the adrenals. Pelvic imaging may prove useful as radioiodinated NP-59 has been shown to concentrate in hyperfunctioning virilizing ovarian neoplasms. IS
Fig 4. gland.
Pheochromocytoma arising in the right adrenal
ent in the imaging of pheochromocytoma." The normal adrenal medulla is rarely visualized with 13II_MIBG scintigraphy, but pheochromocytoma is clearly seen. The radiopharmaceutical is concentrated in the heart, liver, spleen, and adrenal medulla because these organs are rich in sympathetic nerve endings.':" The radiotracer is excreted by the kidneys. Bladder activity may obscure extra-adrenal pheochromocytoma in the
ADRENAL MEDULLARY IMAGING
Pheochromocytoma Pheochromocytoma is a benign neuroectodermal neoplasm usually arising in the adrenal medulla. However, 10% of these tumors are malignant, 10% are bilateral, and 10% are extra-adrenal in location. The tumor may also be associated with neurofibromatosis, tuberous sclerosis, von Hippel-Lindau disease, and MEN syndromes. The diagnosis is made on clinical and biochemical criteria." Because the treatment requires surgical extirpation of the tumor tissue, adrenal medullary scintigraphy provides a noninvasive, specific, and sensitive method for localization of pheochromocytoma whether it is intraor extra-adrenal in origin. I Radioisotope Selection 13II-meta-iodobenzylguanidine C3II-M IBG ) is the radiopharmaceutical agent of choice at pres-
Fig 5. Ectopic pheochromocytoma in the pericardial sac. 13'I-MIBG scintiscan localizes the tumor in the mediastinum (arrow). N, neck.
ADRENAL SCINTIGRAPHY
pelvis and in the bladder, so that the imaging should be performed after the bladder is emptied. Drugs such as reserpine, phenylpropanolamine, tricyclic antidepressants , and cocaine interfere with 13II_MIBG upt ake and should be withdrawn before imaging." 123I-MIBG, which is cyclotronproduced, is much more sensitive for the detection of pheoch romocytoma, but it is expensive and not readily available. In contrast to 13lr_ MIBG, it routinely visualizes the normal adrenal medulla. 18
Fig 6. Bilateral intra-adrenal pheochromocytomas in a patient with multiple endocrine neoplasia syndrome (MEN type II). (AI 13I1-MIBG scintiscan taken 48 hours after injection shows two discrete areas of increased tracer uptake in the upper abdomen . (B) Combined 131I_MIBG and 8OmTc-DTPA scintiscan localizes the kidneys (arrows) and confirms suprarenal location of the areas of increased uptake. corresponding to the adrenals (arrowheads).
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Procedure. 13II-MIBG is available from the University of Michigan. Three drops of Lugol's iodine solution is administrated orally to the patient twice daily to block thyroidal uptake of free radioiodine 24 hours prior to administration of the radioiodinated MIBG and is continued during the entire study. Intravenous injection of 13II_MIBG, 0.5 to 1 mCi/1.7 m 2 body surface area is given in 30 seconds . Imaging is performed with a gamma camera at 48 and 72 hours, at which time most pheochromocytomas become visible. Multiple overlapping images of the body from the skull to the bladder are taken to demonstrate extra-adrenal pheochromocytoma . Iodinated MIBG may reveal bony metastases from pheochromocytoma that are not detectable by 99mTc_M DP bone scanning." If 13II-MIBG scintigraphy reveals activity in the abdomen suggestive of pheochromocytoma, 99mTc-DT PA is injected to visualize the kidneys, thereby increasing the degree of confidence in recogniz ing the adrenal tumor. Additional imaging with 99mTc_ sulfur colloid for detection of liver metastases, and 20l-thallium for delineation of mediastinal pheochromocytoma is useful. I Clinical indications and results. Increased uptake of radioiodinated MIBG suggests the presence of a pheochromocytoma, which may be intra- or extra-adrenal in location (Figs 4 and 5). Multifocal areas of increased uptake are consistent with metastases from a primary malignant
Fig 7. MUltiple peraganglionomas (arrows) in pelvis seen on 1311_MIBG scintiscan 48 hours after injection.
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pheochromocytoma or multicentric primary tumor (Fig 6).18,19 Adrenal medullary imaging with 13II_MIBG provides information about the morphological and functional status of pheochromocytoma, helps to detect extra-adrenal pheochromocytoma, and assesses the extent of the disease by revealing distant metastases and multiple tumors. The technique has a sensitivity of about 85% and specificity close to 100% when pertinent clinical and biochemical data are available, as 13II-MIBG is also localized in other neuroectodermal tumors. I,18,20
Neuroblastoma and Other Tumors Besides pheochromocytoma, neuroblastoma, nonfunctioning paraganglioma (Fig 7), schwannoma, medullary thyroid carcinoma, bronchogenic carcinoma, and carcinoid tumor have also
been shown to concentrate radioiodinated MIBG, and the study may be used for localization of these tumors. I,18,20-22 More important, the study helps to distinguish neuroblastoma from Ewing sarcoma and other small round cell tumors in children since, unlike neuroblastoma, these tumors do not take up the tracer. The sensitivity of MIBG scintigraphy is about 90%, and specificity is close to 100% in the detection of neuroblastoma.P'f" TREATMENT WITH 1311_MIBG
Malignant primary and secondary pheochromocytomas have been treated with high doses (100 to 200 mCi) of radioiodinated MIBG, with varying degrees of success. 18,20,23-25 The radiopharmaceutical has also been used for staging of neuroblastoma and treatment of stage IV neuroblastoma in children.P:"
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12. Gold EM: The Cushing's syndromes: Changing views of diagnosis and treatment. Ann Intern Med 1979;90:829844 13. Luton JP, Mahoudeau JA, Bouchard P, et al: Treatment of Cushing's disease by o,p'DDD. N Engl J Med 1978;300:459-464 14. Conn JW: Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955;45:3-17 15. Carpenter PC, Wahner HW, Salassa RM, et al: Demonstration of steroid-producing gonadal tumors by external scanning with the use of NP-59. Mayo Clin Proc 1979;54:332-334. 16. VanHeerden JA, Sheps SG, Hamberger B, et al: Pheochromocytoma: Current status and changing trends. Surgery 1982;91:367-373 17. Francis JR, Glazer GM, Shapiro B, et al: Complementary roles of CT and 131-I-MIBG scintigraphy in diagnosing pheochromocytoma. AJR 1983;141:719-725 18. McEwan Al, Shapiro B, Sisson JC, et al: Radioiodobenzylguanidine for the scintigraphic location and therapy of adrenergic tumors. Semin Nucl Med 1985;15:132-153 19. Shapiro B, Sisson lC, Lloyd R, et al: Malignant pheochromocytoma: Clinical, biochemical and scintigraphic characterization. Clin EndocrinolI984;20:189-203 20. Hoefnagel CA, V 011te PA, deKraker 1, et al: Radionuelide diagnosis and therapy of neural crest tumors using iodine-131 metaiodo benzylguanidine. J Nucl M ed 1987;28:308-314 21. Munkner T: 131-I-metaiodobenzylguanidine scintigraphy of neuroblastomas. Semin Nucl Med 1985;15:154160 22. Feldman 1M, Blinder RA, Lucas KJ, et al: Iodine
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131-metaiodobenzylguanidine scintigraphy of carcinoid tumors . J Nucl Med 1986;27:1691-1696 23. Kimmig B, Brandeis WE, Eisenhut M, et al: Scintigraphy of a neuroblastoma with 1-131meta-iodobenzylguanidine , J Nucl Med 1984;25:773-775
24. Hattner RS, Huberty JP , Engelstad BL, et al: Localization of m-iodo 31I) benzylguanidine in neuroblastoma . AJR 1984;143:373-374 25. Podrasky AE, Stark DD, Hanner RS , et al: Rad ionuelide bone scanning in neuroblastoma: Skelet al metastases and primary tumor. AJR 1983;141:469-472
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