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ADRENAL CORTICAL TUMORS MARILYN RoUBIDOUX, M.D., AND N. REED DUNNICK, M.D. Diagnostic Imaging Division Department of Radiology Duke University Medical Center Durham, North Carolina

T HE ADRENAL GLANDS ARE PAIRED retroperitoneal endocrine organs located in the perinephric space and surrounded by Gerota's fascia. The right adrenal gland is superior to the upper pole of the kidney, immediately posterior to the inferior vena cava, and medial to the posterior segment of the liver. The left adrenal gland is anteromedial to the upper pole of the left kidney. Although only 5 grams in weight, the adrenal gland consists of two separate endocrine organs, the cortex and the medulla. The cortex is histologically divided into three distinct zones. The zona glomerulosa is the outermost layer and produces aldosterone. The zona fasciculata of the midcortex and the zona reticularis of the inner cortex adjacent to the medulla secrete both cortisol and adrenal androgens. Since computed tomography has become the mainstay of adrenal imaging, familiarity with abdominal cross section anatomy is important. 1 The perinephric fat present in most patients clearly displays the adrenal glands, which appear as thin folded structures with an inverted "Y" or "V" configuration and straight or concave margins (Figure 1). The limbs vary in length and shape at different levels in the same patient. The cortex cannot be distinguished from the medulla by either magnetic resonance imaging or computerized tomography.

ADENOMAS Cortical adenomas are benign tumors which appear as round, yellow, encapsulated masses. Their high lipid content often results in a low density mass.2 Cortical adenomas function as normal adrenal cortex. They respond to feedback inhibition and are referred to as nonhyperfunctioning or "nonfunctioning" adenomas. Address for reprint requests: N. Reed Dunnick, M.D., Box 3808, Radiology Department, Duke University Medical Center, Durham, NC 27710

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Fig. la. Normal adrenal glands. At the level of the celiac axis the left adrenal gland has an inverted "Y" configuration (arrow) while only one limb of the right gland (arrowheads) is seen. Reproduced with permission from Dunnick N.R., McCallum, R.W. and Sandler, C.M.: A Textbook of Uroradiology. Baltimore, Williams & Wilkins, 1991.

Some adenomas are not suppressable, and thus excrete excessive and unregulated amounts of hormone which produces a recognizable clinical syndrome such as Conn's syndrome, Cushing's syndrome, virilization, or feminization. These are referred to as hyperfunctioning or "functioning" adenomas. Functioning adenomas that autonomously produce cortisol produce Cushing's syndrome. Pathologically, these appear as well circumscribed, rounded masses ranging in size from 1 to 9 cm. Approximately 90% are 2 to 5 cm in diameter.3 On computerized tomography, these adenomas are usually homogeneous, unilateral masses (Figure 2). Rarely, a large lesion may contain areas of hemorrhage or necrosis, and an additional finding is increased retroperitoneal fat and fatty infiltration of the liver. Furthermore, a functioning adenoma acts as a negative trophic influence for the rest of the ipsilateral and contralateral adrenal gland, causing partial involution or atrophy of remaining normal adrenal tissue. Bull. N.Y. Acad. Med.

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Fig. lb. Slightly lower, both limbs of the right adrenal gland are visualized (arrowheads) while only the lateral arm of the left gland remains (arrow).

Benign adenomas of the adrenal cortex that produce unregulated aldosterone result in Conn's syndrome. This syndrome was described in 1955 and includes hypertension, hypokalemia, and suppressed plasma renin, all caused by the action of aldosterone on sodium reabsorption.4,5 Pathologically, these are small tumors weighing 20 grams or less. Approximately 90% are 2.5 cm or smaller in size.3 They are histologically distinct from other adenomas, demonstrating a mixture of zona glomerulosa cells.5 They are uniformly benign tumors and produce only aldosterone. The left gland is affected slightly more often that the right. The computerized tomographic appearance of an aldosteronoma is a small, unilateral, homogeneous, round, low density mass (Figure 3). The major difference from a cortisol secreting adenoma is that the aldosteronoma is considerably smaller, commonly less than 2 cm in diameter.6 Nonfunctioning cortical adenomas are often indistinguishable from functioning adenomas by histopathologic examination.7 Nonfunctioning adenomas are reported in 2 to 9% of the population at autopsy.8'9 They are usually small and rarely larger than 5 cm.3 The computerized tomographic Vol. 67, No. 2, March-April 1991

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Fig. 2. Cushing's syndrome. A cortisol secreting adenoma is seen in the right adrenal gland. (arrow) Note the abundant perinephric fat. Reproduced with permission from Dunnick, N.R.: Hyperfunctioning and Nonfunctioning Neoplasms. In: Clinical Urography Pollack, H.M., editor. Philadelphia, Saunders, 1990.

appearance is indistinguishable from that of the functioning adenomas. However, most nonhyperfunctioning adenomas are detected as an incidental finding during tomographic, ultrasound, or magnetic resonance examinations. Thus, differentiating these from other more ominous adrenal masses is a common problem.

CARCINOMAS

Malignant tumors of the adrenal cortex are rare, constituting only 5% of all adrenal cortical neoplasms. These are usually large, weighing 100 to 1,000 grams, and more than 80% exceed 6 cm in diameter at presentation. 10 Invasion of adjacent organs and the inferior vena cava is common.11 Due to their large size and hypovascular nature, these tumors often outgrow their blood supply and undergo central necrosis.11 The histologic appearance varies from mild cellular atypia to wild anaplasia. The distinction of a benign adenoma from a primary adrenal carcinoma is histologically difficult, and such additional criteria as size, growth Bull. N.Y. Acad. Med.

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Fig. 3. Conn's Syndrome. A small low density mass (arrow) is seen in the left adrenal gland.

pattern, presence of vascular or capsular invasion, and endocrine function are used. 12,13 Large or nonhyperfunctioning tumors have a poorer prognosis. The clinical fascination for this rare tumor lies in the multitude of ways in which it may present and the syndromes it produces. Hormonal activity varies widely, ranging from nonfunction to hypersecretion of cortisol, sex hormones, aldosterone, or a combination of hormones.'4 In children, 95% of adrenal cortical carcinomas are hormonally active, while only approximately 50% of adrenal cortical carcinomas in adults produce a recognizable syndrome. 13 Cushing's syndrome is the predominant syndrome of the functional carcinomas. Virilization is most often recognized in women or girls. In addition, children have an unusually high incidence of second primary tumors and congenital anomalies. Most children with an adrenal carcinoma are female and younger than five years of age. Chemotherapy has been disappointing, and the best treatment remains surgical resection. The typical computerized tomographic appearance of an adrenal carcinoma is a large, round, nonhomogeneous mass with a necrotic center (Figure 4). Smaller tumors may be homogeneous. Approximately 25% of Vol. 67, No. 2, March-April 1991

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Fig. 4a. Adrenal Carcinoma. A large right adrenal mass (arrows) with central necrosis is appreciated on this unenhanced CT scan.

tumors show calcification. With intravenous contrast injection, there is heterogenous enhancement. Extension to other organs, as well as the inferior vena cava, is common. "I This appearance, however, is not specific, and the differential diagnosis of a large adrenal lesion also includes metastases, lymphoma, and pheochromocytoma. Magnetic resonance may also be used to examine adrenal carcinomas. T1 weighted images are most useful for defining anatomy. On T2 weighted images, carcinomas have a higher signal intensity (Figure 4b) than normal adrenal tissue or benign adrenal adenomas. 15,16 Determining the organ of origin in large abdominal tumors is often difficult, but magnetic resonance with sagittal and coronal imaging is helpful.

CLINICAL AND RADIOLOGIC EVALUATION OF ADRENAL CORTICAL TUMORS

Earlier radiologic techniques such as excretory urography, sonography, and radionuclide studies have been largely replaced by computerized tomography, and, in selected instances, by magnetic resonance imaging. High resolution tomography is the gold standard for imaging the adrenal glands Bull. N.Y. Acad. Med.

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Fig. 4b. A T2 weighted MR image reveals a high signal intensity (arrows).

because of its ready availability and its high sensitivity in the detection of even small adrenal masses. However, the examination must be tailored to the adrenal glands with finely collimated, contiguous sections. The radiographic evaluation of cortical tumors often falls into one of two clinical situations: evaluation of clinically suspected adrenal hyperfunctional abnormality and characterization of an incidental adrenal mass detected on an examination performed for another indication. Suspected functional abnormalities. Since the adrenal cortex is an active site of synthesis of several hormones, the pathology and classification of an adrenal cortical lesion may be related to its function. Thus, patients may manifest evidence of hormone excess primarily producing: cortisol and presenting as Cushing's syndrome, aldosterone and presenting as Conn's syndrome, or sex hormones and presenting with virilization or feminization. Cushing's syndrome. Endogeneous Cushing's syndrome is manifest by the typical clinical findings of truncal obesity, abdominal striae, muscle atrophy, and elevated plasma or urinary cortisol. In adults a benign but autonomous cortical adenoma causes 10 to 20% of cases. 17 In contrast, 70 to 85% of cases of adult Cushing's syndrome are due to bilateral adrenal hyperplasia, either Vol. 67, No. 2, March-April 1991

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secondary to a pituitary adenoma (Cushing's disease) or the paraneoplastic syndrome of ectopic ACTH secretion caused by a variety of other primary tumors. 17, 18 Biochemical evaluation with measurement of serum ACTH levels and dexamethasone testing usually differentiates adrenal hyperplasia from either pituitary dependent ACTH or ectopic ACTH from autonomous adrenal neoplasms. The role of computerized tomography is to confirm the biological findings by differentiation of bilateral adrenal hyperplasia from a solitary autonomous adrenal adenoma, and to localize the lesion for adrenalectomy. In patients with unequivocal biochemical evidence of Cushing's syndrome, the absence of a focal adrenal mass indicates bilateral hyperplasia. 17,19 Endogeneous Cushing's syndrome is secondary to adrenal carcinoma in 5 to 10% of adult cases and 50 to 80% of pediatric cases. 12,13,18 Although adrenal cortical carcinomas are generally larger than 6 cm and adenomas smaller than 5 cm, no radiologic technique can reliably distinguish a benign hyperfunctioning adenoma from a carcinoma. The radiologic distinction, however, is not crucial because surgery is indicated in all cases of endogeneous Cushing's syndrome with an associated adrenal mass for both symptomatic relief and pathologic diagnosis. Biopsy is not useful, due to the difficulty in distinguishing benign from malignant primary adrenal tumors on a histological basis. Conn's syndrome. Conn's syndrome or primary aldosteronism should be considered in all patients with hypertension and spontaneous hypokalemia. Though the prevalence among all hypertensive patients is only 2% or less, its recognition is important because the hypertension can be severe but surgically curable.5,14 Elevated urinary aldosterone and decreased plasma renin levels are diagnostic. The latter finding is essential in distinguishing primary from secondary aldosteronism. Like Cushing's syndrome, Conn's syndrome can be due to either a hyperfunctioning adenoma (80%) or adrenal hyperplasia. Rare cases of Conn's syndrome due to an adrenal carcinoma have been reported.3,6 Following biochemical documentation of primary aldosteronism, the role of radiology is to distinguish a unilateral aldosterone-producing adenoma from bilateral adrenal hyperplasia because the treatment of hyperplasia is medical and the treatment of a unilateral adenoma is surgical.3,17 A meticulous tomographic examination using narrow collimated contiguous or overlapping sections has a sensitivity of approximately 70% and a specificity near 90%. If a unilateral mass is found, the workup is terminated. If no mass is identified, adrenal venous sampling may be performed. In Bull. N.Y. Acad. Med.

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experienced laboratories adrenal venous sampling is highly accurate,20,21 but the success of imaging has decreased the need for venous sampling and few institutions have maintained the experience needed for this procedure. Computerized tomography should not be used as a screening procedure for Conn's syndrome without an established biochemical diagnosis. The distinction between an adenoma and a carcinoma in a patient with Conn's syndrome is seldom a problem. Carcinomas are usually more than 6 cm in size, compared with an average diameter of 1.5 cm for an aldosteronesecreting adenoma.5 Furthermore, evidence of additional corticosteroid or sex hormone excess is virtually always present in adrenal carcinomas. 19 Adrenogenital syndromes. Adrenogenital syndromes cause virilization or feminization by excess excretion of androgens or estrogens. Although the most common cause for this phenomenon is a group of enzymatic deficiencies leading to congenital adrenal hyperplasia, cortical adrenal tumors, i.e., either benign adenoma or carcinoma, account for approximately 20% of these adrenogenital syndromes. Patients with the tumor-caused syndrome present at a later age than those due to congenital adrenal hyperplasia. Mixed hormonal syndromes, commonly virilization with hypercortisolism, are virtually always caused by carcinoma. Feminizing tumors are much less common and are also malignant. Computerized tomography is indicated to detect and localize an adrenal mass in patients with these syndromes (Figure 5). Although magnetic resonance imaging typically demonstrates a high signal intensity on T2 weighted images in carcinomas, measurements of signal intensity are not yet adequate confidently to differentiate a benign adenoma from a malignant mass. The evidence of endocrine function in itself mandates surgical removal. INCIDENTAL ADRENAL MASSES

One common problem that arises with the widespread use of tomographic scanning is detection of incidental adrenal masses. When an adrenal mass is found, the patient should be examined for evidence of a hormone mediated syndrome such as Cushing's syndrome, Conn's syndrome, or pheochromocytoma. If there is no evidence of hormone oversecretion, the mass is most likely a nonhyperfunctioning adenoma. However, it must be distinguished from an adrenal carcinoma or a metastasis from an occult primary tumor. Radiologic technique cannot definitely distinguish benign from malignant masses, but the size of the mass and evidence of endocrine hyperfunction are helpful. Vol. 67, No. 2, March-April 1991

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Fig. 5. Virilization. A calcified left adrenal tumor (arrow) is detected in a 13-year-old girl.

With hyperfunctioning masses, surgical resection is indicated. Further evaluation is needed with nonhyperfunctional lesions. Lesion size is used to estimate the probability of malignancy. In the absence of an underlying malignancy virtually all lesions smaller than 3 cm will be benign nonfunctioning adenomas. Thus, nonfunctioning masses smaller than 3 cm may be followed by scanning at three, six, and 12 months. Exploration is indicated if the size increases. Conversely, tumors greater than 5 cm in size are suspicious for a primary adrenal cortical carcinoma rather than an adenoma and should be removed. Between 3 and 5 cm, management should be based on an individual evaluation with regard to follow-up versus surgical exploration. 17,19 Percutaneous biopsy is an accurate way to differentiate adrenal cortical neoplasms from metastases. The distinction of an adrenal carcinoma from a benign adenoma is difficult, even by histology, and cannot be made on percutaneous biopsy. Tomography is usually the guiding modality as the adrenal mass and needle path are clearly delineated (Figure 6). The sensitivity of detecting an Bull. N.Y. Acad. Med.

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Fig. 6. Adrenal biopsy. A 20 gauge needle is passed percutaneously through the perinephric space into the adrenal mass.

adrenal metastasis is more than 90%. Normal adrenal cells which are often seen on biopsy of a benign adenoma can be used to confirm this diagnosis if the needle tip is clearly within the mass lesion. REFERENCES 1. Dunnick, N.R., McCallum, R.W., and Sandier, C.M.: A Textbook of Uroradiology. Baltimore, Williams & Wilkins, 1991. 2. Schaner, E.G., Dunnick, N.R., Doppman, J.L., et al.: Adrenal cortical tumors with low attenuation coefficients: a pitfall in computed tomography diagnosis. J. Com. Assist. Tomogr. 2:11-15, 1978. 3. Dunnick, N.R.: The Adrenal Gland. In: Radiology: Diagnosis, Imaging, Intervention, Tavaras, J.M. and Ferrucci, J.T., editors. Philadelphia, Lippincott, 1986.

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4. Conn, J.W.: Primary aldosteronism: a new clinical syndrome. J. Lab. Clin. Med. 45:3-17, 1955. 5. Merrell, R.C.: Aldosterone-producing tumors (Conn's syndrome). Semin. Surg. Oncol. 6:66-70, 1990. 6. Ikeda, D.M. Francis, I.R., and Glazer, G.M.: The detection of adrenal tumors and hyperplasia in patients with primary

aldosteronism: comparison of scintigraphy, CT, and MR imaging. Am. J. Radiol. 153:301-06, 1989. 7. Remer, E.M., Weinfeld, R.M., Glazer, G.M., et al.: Hyperfunctioning and nonhyperfunctioning benign adrenal cortical

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lesions: characterization and comparison with MR imaging. Radiology 171(3):681-85, 1989. Commons, R.R. and Callaway, C.P.: Adenomas of the adrenal cortex. Arch. Intern. Med. 81:37-41, 1948. Hedeland, H., Ostberg, G., and Hokfelt, B.: On the prevalence of adrenocortical adenomas in an autopsy material in relation to hypertension and diabetes. Acta Med. Scand. 184:211-14, 1968. Hamper, U.M., Fishman, E.K., Hartman, D.S., et al.: Primary adrenocortical carcinoma: sonographic evaluation with clinical and pathologic correlation in 26 patients. Am. J. Radiol. 148:915-19, 1987. Dunnick, N.R., Doppman, J.L. and Geelhoed, G.W.: Intravenous extension of endocrine tumors. Am. J. Radiol. 135:471-76, 1980. Chudler, R.M. and Kay, R.: Adrenocortical carcinoma in children. Urol. Clin. N. Am. 16(3):469-79, 1989. Barzilay, J.I. and Pazianos, A.G.: Adrenocortical carcinoma. Urol. Clin. N. Am. 16(3):457-68, 1989. Williams, T.C.: Functional disorders of the adrenal glands: an overview. Semin.

Roentgenol. 23(4):304-13, 1988. 15. Egglin, T.K., Hahn, P.F., and Stark, D.D.: MRI of the- adrenal glands. Semin. Roentgenol. 23(4):280-87, 1988. 16. Smith, S.M., Patel, S.K., Turner, D.A., and Matalon, T.A.: Magnetic resonance imaging of adrenal cortical carcinoma. Urol. Radiol. 11(1):1-6, 1989. 17. Dunnick, N.R.: Adrenal imaging: current status. Am. J. Radiol. 154:927-36, 1990. 18. Bretan, P.N., Jr., and Lorig, R.: Adrenal imaging: computed tomographic scanning and magnetic resonance imaging. Urol. Clin. N. Am. 16(3):505-13, 1989. 19. Moulton, J.S. and Moulton, J.S.: CT of the adrenal glands. Semin. Roentgenol. 23(4):288-303, 1988. 20. Mitty, H.A., Nicolis, G.L., and Gabrilove, J.L.: Adrenal venography: clinical roentgenographic correlation in 80 patients. Am. J. Radiol. 119:564-74, 1973. 21. Dunnick, N.R., Doppman, J.L., Gill, J.R., Jr., et al.: Localization of functional adrenal tumors by computed tomography and venous sampling. Radiology 142:429-33, 1982.

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Adrenal cortical tumors.

119 ADRENAL CORTICAL TUMORS MARILYN RoUBIDOUX, M.D., AND N. REED DUNNICK, M.D. Diagnostic Imaging Division Department of Radiology Duke University Me...
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