MR imaging of the adrenal glands

Magn Reson Imaging Clin N Am 12 (2004) 515–544

MR imaging of the adrenal glands Hero K. Hussain, MD*, Melvyn Korobkin, MD Department of Radiology/MRI B2B311, University of Michigan Hospitals, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA

MR imaging is used commonly for imaging the adrenal glands. Its high-contrast resolution and multiplanar imaging capability enables the detection and characterization of many adrenal masses. The advent of chemical-shift imaging revolutionized the role of MR imaging in characterizing adrenal masses. In this article, the authors discuss the range of MR appearances of common and uncommon adrenal masses, focusing on the nonfunctioning, incidentally discovered mass and its characterization methods. MR imaging is improving continuously. The increasing use of higher strength magnets and the introduction of newer coils, sequences, and techniques will help detect and characterize small adrenal masses, quantify their fat content, and provide exquisite morphologic images of the gland and its vascular supply.

The normal adrenal gland The adrenal gland is composed of two separate functional units: the cortex and the medulla [1]. The adrenal glands are located in the perirenal space [2]. Each gland has a body and medial and lateral limbs, and is visualized as an inverted Y or V structure against the retroperitoneal fat [3]. Normal adrenal body and limbs have concave or straight borders. The width of the body ranges from 6 to 10 mm [2,4], and that of the limbs should not exceed 5 mm [4]. In patients with congenital absence of the kidney, the adrenal * Corresponding author. E-mail address: [email protected] (H.K. Hussain).

glands assume a disk shape, and appear as linear paraspinal structures [5]. Microscopically, the normal adrenal cortex shows three zones: the outermost layer, the zona glomerulosa, produces mineralocorticoids (principally aldosterone); the middle and innermost layers, the zona fasciculata and reticularis, respectively, produce glucorticoids (corticosteroids, androgens, and estrogens). The adrenal medulla secretes adrenaline and noradrenaline [3,6]. Most of the cortical tissue is in the limbs, and the medullary tissue in the body of the gland [4]. Normal cortical cells contain lipid in vesicles and droplets; cells with abundant lipid appear ‘‘clear’’ on routine histology, and those with less lipid appear ‘‘compact’’ [6,7]. On conventional T1-weighted (T1W) and T2weighted (T2W) images without fat suppression, the adrenal glands have homogeneous, low signal intensity in contrast to surrounding high–signal intensity fat, and are isointense or hypointense relative to liver [8]. With fat suppression, the glands appear hyperintense to liver on T1W and T2W sequences. On out-of-phase (OP) spoiled gradient recalled-echo (SGRE) imaging, there is signal loss at the periphery of the gland as a result of fat-water phase cancellation at the interface with adjacent fat [8,9], the well-known ‘‘etching’’ or ‘‘India ink’’ appearance (Fig. 1). This phase cancellation may obscure small adrenal lesions, as well as the limbs of the normal adrenal glands [6], and can be reduced or eliminated on fatsuppressed images. In fact, fat-suppressed T1W SGRE sequences can be used to depict the normal gland and identify small adrenal lesions (Fig. 2). Despite the abundant lipid content of the normal adrenal gland, it has not been possible, in vivo or in vitro, to demonstrate

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Fig. 1. The normal adrenal gland on T1W SGRE. (A) Axial in-phase (IP) (155/4.4/70() and (B) axial out-of-phase (OP) (155/2.2/70(); note the phase-cancellation ‘‘etching or India-ink’’ effect (arrow) at the water-fat interface at the periphery of the gland.

signal loss in normal adrenal limbs on OP or T1W fat-suppressed three-dimensional SGRE images [6].

pertension that is refractory to medical treatment with two agents or more [10]. Adrenal cortical neoplasms

Hyperfunctioning adrenal neoplasms Hyperfunctioning disease of the adrenal glands originates from benign and malignant tumors of the adrenal cortex (Conn syndrome, Cushing syndrome, hyperandrogenism, adrenocortical carcinoma), or medulla (pheochromocytoma). Some hyperfunctioning adrenal tumors present as hy-

Cushing syndrome Cushing syndrome is the clinical and metabolic disorder that results from excess circulating glucocorticoids, regardless of the cause [3]. After excluding exogenous steroid intake, Cushing syndrome is either adrenocorticotropic hormone (ACTH)–dependent (80%) or ACTH-independent. Up to 85% of ACTH-dependent cases are

Fig. 2. Small, left-adrenal adenoma in a patient with biochemical changes of Conn syndrome. The lesion (arrow) is difficult to depict on (A) axial IP and (B) axial OP SGRE (140/4.6 and 2.3/70(), but is clearly seen in (C) axial fatsuppressed T1W SGRE (200/1.2/70(). There was 25% signal-intensity loss in the lesion on quantitative analysis (signal intensity index) indicating a lipid-rich adenoma. Note the normal size of the visualized lateral limb of the left adrenal gland. This adenoma was surgically excised.

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caused by excess ACTH production from a basophil pituitary adenoma (Cushing disease); 15% are caused by ectopic ACTH secretion from a nonpituitary source, usually small-cell lung cancer [11,12]. The adrenal glands in ACTHdependent Cushing syndrome may be normal or show diffuse bilateral hyperplasia [13]. A few patients develop macronodular adrenal hyperplasia [14]. Rarely, a dominant unilateral nodule develops in a hyperplastic gland. ACTH-independent steroid-producing tumors are adrenal adenomas and adrenocortical carcinomas (Fig. 3) in over 95% of cases. Rarely, it can be caused by conditions such as macronodular adrenocortical hyperplasia [14,15], or primary pigmented nodular adrenocortical disease [16]. The main role of imaging in ACTH-dependent Cushing syndrome is to identify the source of ACTH. In ACTH-independent Cushing syndrome, the roles of imaging [17] are as follows:

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1. To distinguish an adenoma from a carcinoma. Adrenal adenomas causing Cushing syndrome are usually greater than 2 cm in diameter, and lesions greater than 4 cm should be regarded as malignant (Fig. 4) [18]. 2. To identify whether there is a single adenoma, which can be resected, or if there is nodular hyperplasia, which is treated medically. Because a unilateral, cortisol-secreting adrenal tumor will result in suppression of ACTH secretion, the ipsilateral and contralateral adrenal glands should be atrophic. If any degree of hypertrophy is present, nodular hyperplasia should be considered [14,19]. Primary hyperaldosteronism (Conn syndrome) Conn syndrome is characterized by hypertension, hypokalemia, and metabolic alkalosis [3]. It is caused by an aldosterone-producing adenoma in 79% of cases, bilateral adrenal hyperplasia in

Fig. 3. Right adrenocortical carcinoma presenting as Cushing syndrome. (A) Axial IP and (B) axial OP SGRE (150/4.2 and 1.8/70(), (C) coronal T2W single-shot fast spin-echo (1/90), and (D) coronal postgadolinium T1W threedimensional SGRE with fat suppression (5/1.2/12(). There is a large, heterogeneous mass on the T1W and T2W images (arrows) with central high T1 signal, and no signal loss on OP imaging. The mass enhances heterogeneously, and invades the lateral wall of the inferior vena cava (arrowhead) on the early postgadolinium image.

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Fig. 4. Small, right adrenocortical carcinoma presenting as abdominal pain. (A) Axial IP SGRE and (B) axial OP SGRE (140/4.2 and 1.8/70(), (C) coronal T2W single-shot fast spin-echo (1/98), and (D) coronal postgadolinium T1W 3D SGRE with fat suppression (4/1.2/12(). A 4.5-cm homogeneous right-adrenal mass (arrows) does not show signal loss on the OP image and is therefore not a lipid-rich adenoma. The mass is slightly heterogeneous on the T2W image, shows rim enhancement postgadolinium, and compresses the renal artery (arrowhead). Findings were confirmed at surgical resection.

20% [3], and adrenocortical carcinoma in less than 1% [20]. Solitary adenomas are resected, and bilateral hyperplasia is treated medically [21]. Conn adenomas usually are small and have a mean diameter of 2 cm (range 0.8–3.8 cm) (Fig. 2) [21,22]. They usually contain intracellular lipid and are visualized best on SGRE in-phase (IP)/OP imaging. The specificity of imaging findings will increase if correlated with endocrinologic studies [23]. Sohaib and colleagues [21] found MR imaging to be 70% sensitive, 100% specific, and 85% accurate for detecting adenomas and differentiating them from bilateral adrenal hyperplasia in patients with biochemical evidence of Conn

syndrome. The adrenal glands were larger, and had a nodular or smooth contour in adrenal hyperplasia, compared with smaller glands, and a single nodule in cases of adenoma. Signal loss on OP imaging was seen in both conditions. Improved spatial resolution of MR imaging may demonstrate nodularity of the adrenal glands and result in a false diagnosis of adrenal hyperplasia in patients with solitary adenomas. Such nodules are sometimes unrelated and seen with increasing age and hypertension [21,24,25]. Falsepositive diagnosis of a solitary adenoma may occur in bilateral adrenal hyperplasia and a dominant unilateral macronodule.

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In view of the high specificity of MR imaging findings, several authors [21,24] have recommended the following in patients with biochemical evidence of Conn’s syndrome: if a unilateral adrenal mass is identified on MR imaging with a normal contralateral gland, unilateral adrenalectomy can be recommended; if MR imaging depicts bilateral adrenal masses, or a unilateral adrenal mass with a hyperplastic contralateral gland, venous sampling is recommended. Adrenogenital syndrome The most common cause of virilizing states in childhood is congenital adrenal hyperplasia. Androgen-secreting tumors are rare. When present, they are carcinomas and rarely adenomas [3]. Congenital adrenal hyperplasia most commonly results from 21b-hydroxylase deficiency [12],

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which is essential for the production of cortisol and aldosterone. This leads to excess ACTH and chronic adrenocortical stimulation, with subsequent adrenal hyperplasia. In long-standing cases, transformation into adenoma or carcinoma can occur [3,26]. Adrenocortical carcinoma This is a rare, highly malignant tumor [3]. Patients often present with abdominal pain or mass, and the tumors are usually large at time of diagnosis. Eighty percent of adrenal cortical carcinomas are functional, resulting in atrophy of the contralateral adrenal gland [12]. On imaging, these tumors usually exceed 6 cm in size and have variable, usually heterogeneous appearance on T1W, T2W, and gadolinium-enhanced imaging (Fig. 5). They may contain areas of hemor-

Fig. 5. Left adrenocortical carcinoma presenting as a mass. (A) Axial OP SGRE (140/1.8/70(), (B) axial T2W fastrecovery fast spin-echo (2500/98), (C) coronal postgadolinium three-dimensional SGRE with fat suppression (4/1.2/12(), and (D) sagittal postgadolinium two-dimensional SGRE with fat suppression (210/1.2/70(). There is a large rightadrenal mass (arrows) with heterogeneous T1 and T2 signal intensity and enhancement. Note the lack of enhancement of the central portion of the mass ‘‘central scar’’ (asterisk). Multiplanar imaging shows the adrenal origin of the mass.

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Pheochromocytoma Pheochromocytoma is the most common tumor of the adrenal medulla. These tumors secrete epinephrine and norepinephrine [29]. Patients can be asymptomatic or present with various symptoms including paroxysmal hypertension, flushing, tachycardia, headaches, diaphoresis, and chest pain [30]. Pheochromocytomas are thought to be the cause of hypertension in 0.1% to 0.5% of patients with newly diagnosed hypertension. These tumors occur with equal frequency in men and women, usually in the third and fourth decades of life [30].

The diagnosis is made by biochemical assay of catecholamines and their metabolites in blood or urine. Pheochromocytomas have been called ‘‘10% tumors’’ because approximately 10% are bilateral, extra-adrenal, familial, malignant, or occur in children [29,30]. The incidence of malignancy is higher in extra-adrenal tumors, and those larger than 6 cm [3]. Ninety percent of pheochromocytomas are sporadic; the remainder are inherited as an isolated disorder or associated with multiple endocrine neoplasms IIa, IIb, or III syndrome; von Hippel-Lindau; and neurofibromatosis type 1 [3,31]. The role of imaging is to localize these tumors. If laboratory tests indicate the presence of a pheochromocytoma, imaging of the adrenal glands is performed because it is the most common site for such tumors. If no adrenal lesion is found, imaging is continued down through the organ of Zuckerkandl to encompass all chromafin cellbearing tissue along the lower abdominal aorta and into the iliac vessels, followed by imaging through the bladder, another site of tumor [29– 32,33]. Intrapericardial pheochromocytomas are rare (Fig. 8) [34]. Pheochromocytomas are usually 3 cm or larger, can demonstrate areas of necrosis or hemorrhage, and may contain fluid–fluid levels [29]. Small pheochromocytomas are often homogeneous, and large tumors have central necrosis [35]. Rarely, pheochromocytomas are cystic, and the diagnosis should be considered when evaluating a cystic mass of the adrenal gland [36]. On MR imaging, these tumors are usually hypointense on

Fig. 6. Axial postgadolinium fat-suppressed T1W SGRE (190/1.2/70() image showing a heterogeneously enhancing right adrenocortical carcinoma (arrowhead) with bland, low signal intensity, nonenhancing, thrombus in the inferior vena cava (arrow).

Fig. 7. Axial postgadolinium fat-suppressed T1W SGRE (200/1.5/70() image showing a heterogeneously enhancing right adrenocortical carcinoma involving the right diaphragmatic crus (arrow), which is thickened and irregular, and enhances intensely with gadolinium.

rhage that manifest as high signal intensity on T1W imaging. Central necrosis manifests as a central scar area of low T1 and heterogeneous high T2 signal intensity, without enhancement postgadolinium. Peripherally enhancing nodules also can be seen [27,28]. Adrenocortical carcinoma occasionally contains foci of fat or intracytoplasmic lipid, and can demonstrate signal loss on fat-suppressed and OP imaging [12,27]. Metastasis to liver, lung, and lymph nodes often is seen at time of diagnosis [28]. Vena cava, renal vein, liver, and diaphragm invasion can occur in these tumors (Figs. 6 and 7) [28]. The multiplanar capability of MR imaging is useful for determining the adrenal origin of large retroperitoneal masses (see Fig. 5), and coronal gadoliniumenhanced imaging is helpful to display the extent of caval involvement (see Fig. 3). Adrenal medullary neoplasms

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Fig. 8. Presumed intrapericardial pheochromocytoma in a patient with hypertension, elevated catecholamines, and family history of isolated pheochromocytoma. Metaiodobenzylguanidine scan showed mediastinal uptake. (A) Axial and (B) sagittal T2W triple-inversion recovery (1860/80/blood inversion time: 650) images showing a 2.5-cm mass in the posterior pericardium (arrows). The mass has high homogeneous T2 signal intensity. The patient refused surgery.

T1W images compared with liver, markedly hyperintense on T2W images, and do not show signal loss on OP imaging (Fig. 9). Early studies suggested that the marked uniform signal hyperintensity on T2W imaging ‘‘light bulb’’ can be used to distinguish pheochromocytomas from other adrenal masses [37,38]. Subsequent studies showed that there is an overlap between the T2 signal intensity of pheochromocytomas and other adrenal tumors [39–41] and that a pheochromocytoma cannot be excluded on the basis of a lack of high signal intensity on T2W MR imaging [39]. Reduced T2 signal intensity can result from internal hemorrhage [30]. Pheochromocytomas are rich in intracellular water, and have intratumoral cystic regions, accounting for their high signal on T2W imaging [40]. These tumors are highly vascular, and exhibit marked enhancement after gadolinium administration (Fig. 10) [40]. Similar to the nonionic CT contrast medium (iohexol) [42], gadolinium does not result in increased circulating catecholamine levels, and can be given to patients with pheochromocytoma without the need for specific alpha- and beta-adrenergic blockade before scanning. MR imaging remains useful for detecting extra-adrenal paraganglionomas and recurrences after resection, given their high signal intensity on T2W images [18]. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma Neuroblastoma is the most common extracranial solid tumor of childhood. Ganglioneu-

roblastomas contain elements of malignant neuroblastoma and benign ganglioneuroma [3,29]. Adult ganglioneuroblastoma is rare and occurs mostly in the abdomen [43]. Ganglioneuromas are rare benign neoplasms of sympathetic ganglia [35]. MR imaging features of neuroblastomas and ganglioneuroblastomas are nonspecific. These tumors are predominantly hypointense or isointense to muscle on T1W imaging, and demonstrate heterogeneous hyperintense T2 signal intensity. Areas of T2 hypointensity relate to hemorrhage and fibrous content of the tumor. Following gadolinium, these tumors enhance intensely and heterogeneously. With neuroblastomas, encasement of major vessels, invasion of adjacent organs, and distant metastasis to bone, bone marrow, liver, lymph nodes, and skin can be seen on MR imaging. The lack of ionizing radiation makes it particularly suitable for children [3,29]. Neuroblastoma can occur rarely in adults and pursues an aggressive clinical course [44]. Ganglioneuromas have a whorled appearance on T1W and T2W imaging and variable T2 hyperintensity, and a capsule can be seen occasionally on postgadolinium T1W images [45]. Nonfunctioning adrenal neoplasms Adenomas Nonfunctioning adrenal adenoma is the most common adrenal mass. It has prevalence in the general population of approximately 3% [3], and

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Fig. 9. Left pheochromocytoma in a 38-year-old patient presenting with paroxysmal hypertension. (A) Axial IP SGRE and (B) OP SGRE (120/4.4–2.1/70(), and (C) axial T2W fat-suppressed fast spin-echo (4200/98(). A 2-cm left adrenal mass (arrows) does not show signal loss compared with spleen on OP imaging, and has high signal intensity on the T2W image, almost as bright as cerebrospinal fluid. The mass was surgically resected.

is found in 3% to 8.7% of people at autopsy [35]. The number and size of these nodules increase with age, and their frequency increases in obese diabetic patients and elderly women [3,16]. Distinguishing adrenal adenomas from nonadenomas (metastases and pheochromocyroma) on MR imaging has been the focus of many studies since the mid-1980s [25,46–55]. Many adrenal masses are detected incidentally on cross-sectional imaging, thus called ‘‘incidentalomas’’ [56,57], and most are benign adenomas even in patients with extra-adrenal malignancy [58,59]. Adrenal masses of at least 1 cm are discovered in 0.6% to 1.5% of the population during abdominal CT [57]. The adrenal gland also is a common site for metastasis, most commonly from lung carcinoma. Therefore, characterization of an adrenal mass in a patient with extra-adrenal malignancy is essential because the nature of the adrenal mass may determine if the patient can undergo curative therapy, especially if it is the only site of possible metastasis. Early attempts to characterize adrenal masses on MR imaging using the T1 and T2 signal

intensity of the mass [25,51–54] and calculated T2 measurements [60] showed a significant overlap between the imaging characteristics of adenomas and nonadenomas. These tests had low specificity, which is not desirable when the task of the test is to differentiate between adenoma and metastases [61,62]. Likewise, the results of gadolinium-enhanced imaging have not been shown to be reliable for adrenal mass characterization [63–66]. Chemical-shift imaging Chemical-shift imaging (CSI) is a technique used to identify intracytoplasmic lipid within tissues [9], and is the most sensitive and specific MR imaging technique for characterization of adrenal adenomas [11,25,47–50,61,67] because most adenomas are rich in intracellular lipid. Chemical shift refers to the nuclear magnetic resonance (NMR) frequency difference, Dm, between water and fat for a given magnetic field strength. This difference causes the relative orientation of fat and water magnetization vectors to change by 180( at time s = 1/(1/2Dm). Typically, images are acquired IP where water and fat

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Fig. 10. Right pheochromocytoma in a patient with uncontrolled hypertension. (A) Axial IP and (B) axial OP SGRE (160/4.4–2.2/90(), (C) axial T2W fat-suppressed fast spin-echo image (4800/98), and (D) coronal postgadolinium T1W three-dimensional SGRE with fat suppression (5/1.2/12(). A 4-cm right-adrenal mass (arrows) does not show signal loss compared with kidney on OP imaging. The signal intensity of the mass cannot be compared with the liver because of hemosiderosis following multiple recent blood transfusions causing diffuse low signal intensity of the liver on all sequences. The mass enhances intensely on the 2-minute postgadolinium image.

constituents combine to yield a stronger signal in voxels where they coexist, and OP where water and fat oppose and cancel each other, to yield a weaker signal. At 1.5 Tesla, the NMR frequency difference is about 224 Hz; thus, the OP and IP phenomenon occurs every 2.27 milliseconds. Adrenal adenomas contain variable amounts of intracytoplasmic lipid (cholesterol, fatty acids, and neutral fat) in clear and compact cells [7]; most have a substantial amount, but occasionally they are lipid-poor [7,25,68,69]. Other tumors —including adrenocortical carcinoma; metastases from hepatocellular carcinoma, clear cell carcinoma of the kidney, and liposarcoma—and pheochromocytoma may contain small amounts of lipid [11,70–72], usually not exceeding 6%

[68,69]. The lipid content causes signal-loss on OP imaging, aiding the characterization of adrenal adenomas [7]. On MR imaging, most adenomas do not exceed 3 cm in diameter and are round or oval, with smooth and well-defined margins [35]. Most display homogeneous signal intensity on T1W and T2W images, and show homogeneous signal loss on OP imaging (Fig. 11) except for lipid-poor adenomas (Fig. 12). Occasionally, the signal loss can be heterogeneous (Fig. 13). Rarely, adenomas may contain cystic areas, or undergo hemorrhage or degeneration (Fig. 14) [35]. Analysis of signal loss in an adrenal mass is performed by comparing the signal intensity of the mass on OP imaging to that on IP, and to the signal

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Fig. 11. Small, incidentally discovered, bilateral adrenal adenomas in a patient without known malignancy. (A) Axial IP and (B) axial OP SGRE (155/4.4 and 2.2/70(). There is diffuse signal loss (arrows) in both adrenal lesions on OP compa red with IP and spleen, indicating bilateral lipid-rich adenomas. Note mild fatty infiltration of the liver (asterisk) and an area of parenchymal sparing (arrowhead).

intensity of an adjacent organ (liver, spleen, or kidney) that does not contain fat and is not expected to show signal loss on OP imaging. This comparison is either performed qualitatively by simple visual analysis, or quantitatively by using region-of-interest (ROI) measurements. When placing ROI over adrenal masses, it is essential to avoid the phase cancellation at the edge of the mass on OP images. MR signal intensity units are arbitrary; therefore, comparing the signal intensity of the adrenal mass to an internal reference is necessary for accurate analyses. This also helps control variations in transmit power and receive gain when these parameters were not fixed between the IP and OP sequences [50]. If only visual inspection of the mass on IP and OP is used to assess for signal loss, it is necessary to have the same contrast window width and level on both images, because variable image contrast may influence the perceived signal. Differences in image contrast do not influence quantitative measurements.

The initial study by Mitchell and colleagues [25] evaluating CSI for characterization of adrenal masses assessed for the presence of signal loss in adrenal masses qualitatively and quantitatively, relative to a reference tissue (liver and skeletal muscle). Qualitatively, the authors detected signal loss only in benign adrenal cortical masses (adenoma and myelolipoma); quantitatively, they detected more signal loss in adenomas than metastases. The authors found that the sensitivity for detecting lipid was greater for OP gradient recalled-echo (GRE) imaging than for fatsuppressed spin-echo (SE) imaging. The latter finding is expected because only the signal from fat is removed from fat-suppressed images, whereas in addition to the signal from lipid, an equal amount of water signal is removed from OP imaging, making it more sensitive for small amounts of lipid. Furthermore, the performance of fat-saturation techniques depends on the homogeneity of the magnetic field, and the absence of perturbations within the patients, such as air or metallic artifact. The authors concluded that

Fig. 12. Small, lipid-poor, left-adrenal adenoma on (A) IP and (B) OP SGRE (135/4.4 and 2.0/70(). Note the lack of signal change in the adenoma (arrow) on the OP image compared with IP and spleen. The patient had no history of extra-adrenal malignancy, and the lesion was unchanged on the 1-year follow-up CT study.

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Fig. 13. Small, right-adrenal adenoma on (A) IP and (B) OP SGRE (150/4.4 and 2.1/90(). Note the focal signal loss (arrow) in the medial aspect of the mass on the OP image compared with IP. The patient had no history of extra-adrenal malignancy. The lesion was called probable adenoma on the initial study, and remained stable on the 8-month follow-up MR study.

Fig. 14. Degenerated right-cortical adenoma with hemorrhage on (A) IP and (B) OP SGRE (155/4.4 and 2.2/70(), (C) axial T2W fat-suppressed, fast-recovery, fast spin-echo (2900/89(), and (D) coronal postgadolinium T1W threedimensional SGRE with fat suppression image (5/1.2/12(). Note the heterogeneous signal intensity and enhancement of the mass on all sequences. The mass was called suspicious for adrenal cortical carcinoma, but found to be a degenerated adenoma on surgical pathology.

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qualitative analysis of signal loss is as good as quantitative analysis. Bilbey and colleagues [49] and Mayo-Smith and colleagues [50] applied a similar quantitative analysis method to that used by Mitchell and colleagues [25] to differentiate adrenal adenomas from nonadenomas. These authors used the spleen, in addition to liver and skeletal muscle, as internal references. Both studies concluded that the spleen is a more reliable internal reference than liver and skeletal muscle because it does not undergo fatty infiltration. Bilbey and colleagues [49] addressed the issue of splenic iron, which results in low signal intensity of the spleen on the T1W GRE images, especially the longer echo time (TE) image, and concluded that the presence of splenic hemosiderosis will not result in a nonadenoma being characterized as an adenoma using their calculation method. Mayo-Smith and colleagues [50] also used qualitative analysis for assessment of signal loss and found it to be as good as quantitative analysis, which they suggested is only necessary for equivocal cases and inexperienced readers. Leroy-Willig and colleagues [48] in a letter were the first to suggest that using only a qualitative measure may introduce errors in characterizing masses. This is because the apparent signal intensity on OP imaging relates not only to the amount of fat, but also to the effect of T1 relaxation introduced by imaging parameters. The authors recommended that to get the most accurate results, a single slice IP and OP GRE image at the same level during suspended respiration, using the parameters specified in Table 1 and similar machine calibrations, should be used. The ratio of the signal intensity of the adrenal mass on OP and IP images will allow classification of lesions according to their lipid content; at a ratio of less than 0.4, the probability of benignity is high. Unlike the prior studies, Tsushima and colleagues [47] assessed signal loss in adrenal masses quantitatively using the IP image as the internal reference (signal intensity index [SII]). The authors were able to do so because they used the same sequence, with similar parameters except for the TE value, and the same transmitter power and receiver gain, for the IP and OP acquisitions. The authors characterized all masses with 100% accuracy, using a 5% signal loss as the minimal threshold for adrenal adenomas. The authors hypothesized that the SII of nonadenomas should be less than 0%, except for lipid-containing

metastases, but found that three of the nonadenomas had positive SII greater than 0%, and attributed this to inconsistencies in radiofrequency pulses and inadequate image quality. The usefulness of CSI for differentiating adrenal adenomas from nonadenomas using the liver as internal reference was confirmed by Reinig and colleagues [11] and Korobkin [7,61] and colleagues. Both groups showed some overlap between adenomas and nonadenomas. Reinig and colleagues [11] did not confirm the usefulness of the SII analysis method proposed by Tsushima and colleagues [47], or the signal intensity ratio proposed by Leroy-Willig and colleagues [48]. Korobkin and colleagues [7,61] found that qualitative analysis of signal loss is as reliable as quantitative analysis. Outwater and colleagues [73], using qualitative analysis only, confirmed the utility of the spleen as an internal reference to determine signal loss in adrenal adenomas on CSI. In another study 1 year later [67] using quantitative analysis only, the same authors reconfirmed the utility of the spleen and favored using it over the liver because of potential errors in assessment of signal loss introduced by hepatic steatosis. The usefulness of the quantitative SII calculation introduced by Tsushima and colleagues [47] to distinguish adrenal adenomas from nonadenomas was confirmed in several studies: Heinz-Peer and colleagues [74], Slapa and colleagues [65], Namimoto and colleagues [55], and Fujiyoshi and colleagues [75]. Heinz-Peer and colleagues [74] also found the SII and the adrenal-spleen ratio to be almost equally effective in characterizing adrenal masses, and that qualitative analysis is as useful as quantitative analysis. Slapa and colleagues [65] found the SII to be more useful than adrenalspleen/muscle ratios. The authors found that at a minimal SII threshold of 6% for adenomas, there was minimal overlap with some malignant adrenal lesions. This was attributed to exaggerated signal loss on the OP image (TE 11 milliseconds) compared with IP (TE 9 milliseconds) resulting from T2* on the longer TE image, and the presence of a small amount of lipid within adrenocortical carcinoma and some metastatic tumors. In the studies by Namimito and colleagues [55] and Fujiyoshi and colleagues [75], the SII calculation provided a 100% accuracy for differentiating adenomas from nonadenomas using different threshold values for signal loss; more than 0% for adenomas by Namimito [55], and between 11.2% and 16.5% by Fujiyoshi and colleagues [75].

Table 1 Chemical shift imaging studies performed for characterization of adrenal masses Quantitative CSI analysis method

Magnet and sequences

Mitchell [25]

Yes

1.5 T IP: SE (400–600/11–22) 7–10 mm section/2 gap 256
128–192 matrix CSI: GRE OP (59–142/ 2.3–2.5/90()—section/ gap and matrix not specified, and/or SE þ FS (400–600/11–22)

Adrenal-liver ratio Adrenal-muscle ratio

Tsushima [47]

No

LeroyWillig [48]

No

Reinig [11]

No

1.5 T, body coil IP: FLASH (100/13/20() OP: FLASH (100/11/20() 5 mm section/1 gap 256
192 matrix 20 sec breath-hold CSI: IP (150/4.3/90() OP (150/2.3/90() Section/gap not specified 256
128 matrix 20 sec breath-hold 1.5 T IP: GRE (50/5/90() OP: GRE (51/7/90() þ FS 5mm section/1 gap 256
192 matrix 10–20 breath-hold

Korobkin [61]

Yes

Study

Results and preferred method

[(CSI.SA/SL/T1.SA/ SL)  1]
100 [(CSI.SA/SM/T1.SA/ SM)  1]
100

Negative numbers indicate presence of lipid

Signal intensity index

[(SIP-adrenal  SOPadrenal )/ SIP-adrenal]
100

>5%

26 of 27 benign cortial masses, but none of the nonadenomas, displayed signal loss on at least one CSI image. OP is slightly more sensitive than SE þ FS for demonstrating signal loss. Qualitative analysis is as good as quantitative. 100% accuracy for differentiating adenomas from nonadenomas.

Signal intensity ratio

SI on OP/SI on IP

<0.4

Adrenal-liver ratio Signal intensity index Signal intensity ratio

Similar to [25] i.e. [(OP.SA/SL/IP.SA/ SL)  1]
100 Similar to [47] Similar to [48]

Adrenal-liver ratio Adrenal-muscle ratio

Similar to [25] Similar to [25]

Negative numbers indicate presence of lipid Not specified (probably similar to [47] and [48]) >12% decrease in A-L ratio >20% decrease in A-M ratio

Letter, no results. Authors suggest adenomas contain >10% lipid, and malignant lesions <6%. Best single method for adenoma metastases is A-L ratio (Az 0.9  0.05).

The >12% A-L ratio threshold has a 84% sensitivity and 100% specificity for adenomas, compared to 26% sensitivity and 100% specificity for the >20% A-M ratio threshold. Qualitative analysis is as good as quantitative. (continued on next page)

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1.5 T, body coil IP: SGRE (68–160/4.2–4.9/60() or SE (300–400/10–24) GRE: 4–5 mm section 256
192 matrix breath-hold CSI: SGRE OP (68–160/2.1– 2.9 or 6.3/60() or SE þ FS (SE: 4–5mm section/ 0–2 gap 256
192 matrix)

Threshold for adenoma

Formula

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Qualitative analysis

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Study

Qualitative Magnet and analysis sequences

Bilbey [49]

No

0.5 T IP: SE (500/20) OP: GRE (142/6.3/90() 5 mm sections/1 gap 256
128 matrix antiperistalsis agent given

Mayo-Smith [50]

Yes

1.5 T IP: SGRE (110–150/ 4.6 or 5/no flip angle specified) OP: GRE (110–150/2.3 or 7/no flip angle specified) 256
192 matrix Section/ gap not specified 16–20 breath-hold

Quantitative CSI analysis method

Formula

Threshold for adenoma

Adrenal-liver SI ratio Adrenal-muscle SI ratio Adrenal-spleen SI ratio

[(SA/S reference tissue) OP / (SA/S reference tissue)IP]

A-S SI ratio <0.8

Adrenal-liver ratio Adrenal-muscle ratio Adrenal-spleen ratio Signal intensity index

Similar Similar Similar Similar

to to to to

[25] [25] [25] [47]

Results and preferred method

Mean (and range) SI ratios of adenomas: A-L: 0.47 (0.23–0.97) A-M: 0.44 (0.22–0.66) A-S: 0.45 (0.27–0.73) At A-S threshold <0.8, no overlap between adenoma and nonadenoma (100% accuracy). A-S ratio < 25 Mean SI ratio for adenoma and  0 vs metastases (p < 0.001 for all): A-S ratio: 48 vs 4 A-L ratio: 31 vs 3 A-M ratio: 37 vs 9 SII: 50% vs 18% Best single method for adenoma versus metastasis is A-S ratio (Az 0.97). At A-S thresholds of <25 and <0 for adenomas, sensitivity, specificity, and accuracy for metastasis was (100%, 82%, and 89%) and (50%, 100%, and 80%) respectively. Qualitative analysis is as good as quantitative.

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Table 1 (continued)

McNicholas [78]

No

Outwater [67] No

Korobkin [7]

Yes

MR imaging correctly classified 10/13 masses  0 HU as benign, 10/11 masses 1–20 HU as 4/5 benign and 6/6 malignant, and 13/13 masses >20 HU as malignant. Qualitative analysis for definite or probable diagnosis of a benign lesion has a mean sensitivity of 87%, specificity 92%, PPV 95%.

1.5 T, body coil IP: SE (400–550/10–12) or SGRE (86–171/4.2/70–90() OP: SGRE (35–155/ 2.2–2.9/90() 5–10 mm section/0–2 gap 256
128-192 matrix 10–20 breath-hold 1.5 T, body and phased array coils IP: SE (400–583/10–12) or SGRE (45–180/4.2/60-90() OP: SGRE (45–180/1.4–3.1/ 60-90() 4—10 mm section/0–2 gap 256
128–192 matrix breath-hold 1.5T, body coil IP: SGRE 68–160/4.2–4.9/ 60–90( OP: SGRE 68–160/2.1–2.9 or 6.3/60–90( 5—10 mm sections/0–2 mm gap 256 x 128–192 matrix 8–20 breath-hold

Adrenal-spleen SI ratio Adrenal-liver SI ratio

[(SA/ SS)OP / (SA/ SS)IP] [(SA/ SL)OP/(SA/ SL)IP]

 0.71

Significant correlation between nonenhanced CT values and A-S SI ratio (0.85). Neither technique is more accurate: Az CT(17 HU) 0.93, Az MR imaging 0.96.

Adrenal-liver ratio

Similar to [25]

Threshold not specified

Mean signal loss for adenoma 25%  17 (non-functioning 28%  17, hyper-functioning 21%  20) Lipid-rich cell content of adrenal masses accounts for low attenuation on unenhanced CT and signal loss on CSI. No difference in fat content of nonfunctioning and hyper-functioning adenomas. Qualitative analysis results similar to quantitative analysis. (continued on next page)

No quantitative analysis

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Outwater [73] Yes

[(SA)/SS)OP/ (SA/SS)IP]
100

1.5T Adrenal-spleen ratio IP: SGRE (110–150/4.6 or 5/ Similar to [49] flip angle not specified) OP: SGRE (110–150-2.3 or 7) 10-mm section/0 gap 256
192 matrix breath-hold

530

Study

Qualitative Magnet and analysis sequences

Quantitative CSI analysis method

Formula

Threshold for Results and adenoma preferred method

Slapa [65]

1.5T IP: FLASH (104/9/20) OP: FLASH (104/11/20) breath-hold

Signal intensity index Adrenal-liver ratio Adrenal-muscle ratio

Similar to [47] Similar to [25] Similar to [25]

SII $ 6%

Heinz-Peer [74] Yes

1.0T IP: GRE (25/6.9/30() OP: GRE (25/3.5/30() Sections/gap not specified 256
128 matrix breath-hold

Adrenal-spleen ratio

Similar to [25], i.e. [(SA)/SS)OP/ (SA/SS)IP-1]
100 Similar to [47]

Not specified

1.5T, circular polarized body-array coil Double-echo FLASH (150/2.7 and 5.2/70() 6 mm sections/1.2 gap 256
128 matrix

Signal intensity index

(SIP-adrenal  SOPSIP-adrenal

>0

Namimoto [55] No

Signal intensity index

adrenal

)/

SII more useful than A-L and A-M ratio for characterization of adrenal masses. One metastases and one neuroblastoma had SII of 7.6% and 9.3% respectively. Mean signal loss using A-S ratio is: adenoma 36%  36.7; nonadenoma 3.7%  14.4 (p < .001) Mean signal loss using SII is: adenoma 33.5%  32.0; nonadenoma 8.5%  16.9% (p < 0.001) Mean MR imaging sensitivity, specificity, and accuracy for differentiating benign from malignant adrenal masses is 91%, 94%,and 93%, respectively. Results of both quantitative analyses methods are comparable. Qualitative analysis is as good as quantitative. SII adenoma 0.36  0.18; metastasis 0.15  0.12; pheo 0.07  0.08 Sensitivity, specificity and accuracy of 100% for differentiating adenoma from nonadenoma. Mean fat fraction is 26.5% in adenomas, and 0% in nonadenomas.

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Table 1 (continued)

No

1.5T, phased array coil IP: FLASH (133/4.4/75() OP: FLASH (133/2.2/75() 6 mm sections/0.6 gap 256
134 19 breath-hold

Signal intensity index Adrenal-spleen ratio Adrenal-muscle ratio Adrenal-liver ratio

Israel [79]

Yes

1.5T, torso phased array coil IP: GRE (152–200/4.8–5.3/ flip angle not specified) OP: (152–200/2.1–2.7) 4–8 mm sections/0.6–2 gap 256
128 breath-hold

Adrenal-spleen ratio Signal intensity index

Haider [81]

No

Adrenal-kidney ratio 1.5T IP: SGRE (80–200/4.2–4.6/ 75–90() OP: SGRE (80–200/2.1–2.3/ 75–90() and dual-echo gradient echo 5–7 mm sections/0 gap 256
160-192 breath-hold

11.2%–16.5% SII of all adenomas > 16.5%; nonadenomas < 11.2%. SII has 100% accuracy, and is the best quantitative method to differentiate adenoma from metastatic tumor: Az SII = 1.00 Az A-S ratio = 0.984 Az A-M ratio = 0.949 Az A-L ratio = 0.932. Similar to [67] < 0.71 Sensitivity and specificity for Similar to [47] >16.5% diagnosing lipid-rich adenoma is 100% and 100% for A-S ratio; 100% and 67% for SII. 62% (8/ 13) of CT lipid-poor adenomas (> 10 HU) were characterized as lipid-rich adenomas on CSI. Qualitative analysis less sensitive than quantitative for adrenal mass characterization. [(SA/SK) OP / (SA/SK)IP]
$ 20% Overall 67% MR imaging 100 sensitivity for adenomas >10 – 30 HU. Poor sensitivity for adenomas > 30 HU. Specificity of MR diagnosis of adenoma is 100%. Similar Similar Similar Similar

to to to to

[47] [25] [25] [25]

The table includes the sequences, sequence parameters, analyses methods, formulas for quantitative analysis, threshold values for adenomas, results, and recommendations of the studies. Abbreviations: A, adrenal; Az, area under ROC curve; CSR, chemical shift ratio; FLASH, fast low-angle shot (Siemens); FS, fat suppression; L, Liver; M, Muscle; PPV, positive predictive value; S, signal intensity; SII, signal intensity index; S, spleen.

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Fujiyoshi [75]

531

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Slapa and colleagues [76] performed receiver operating characteristics (ROC) analysis of four MR imaging parameters used to differentiate adenomas from nonadenomas, including size, adrenal-liver T2 signal intensity ratio, SII, and maximum contrast washout. The authors found the best MR imaging performance for characterization of all adrenal masses was the combination of mean tumor diameter and adrenal-liver T2 signal intensity ratio (area under ROC [Az] 0.987), and mean tumor diameter and SII for characterizing nonhyperfunctioning adrenal adenomas (Az 0.991). It seems from the previous studies that the adrenal-spleen ratio and SII are the most reliable quantitative analysis methods, but the optimal thresholds for diagnosing adenomas have not been determined. Various thresholds ranging from 25 to 0.8 for adrenal-spleen ratio calculation [49,50,67], and from 1% to 16.5% for SII [47,55,65,75] have been used. Other authors [11,50,74] have found major overlap between the SII of adenomas and nonadenomas. It is unclear why the reported thresholds are so variable. It may relate to the variable T1W of the SGRE sequences used by the investigators. Increasing the T1W (by increasing the flip angle or repetition time [TR] value) results in overestimation of the fat content. Furthermore, the introduction of T2* signal loss on the longer OP than IP echo time image, especially in the older studies, would overestimate systematically the amount of fat, if T2* measurements are not taken into account. This is because the OP signal measurements will be erroneously low. Conversely, T2* signal loss, when present, will result in underestimation of the fat content of adrenal masses when a shorter OP than IP echo time is used. This is related to the erroneous low signal intensity of the mass on the IP image. Image noise, partial volume averaging related to the resolution limits of the acquisitions and surrounding phase-cancellation at the fat-water interface, and operator selected ROI also may affect the signal intensity measurements. All these issues raise the question of applicability of a single threshold value for different MR scanners. See Table 1 for the sequences, sequence parameters, types of analyses of CSI, signal intensity calculation formulas, and threshold values. Although some studies [7,25,50,61,74] found qualitative analysis of signal loss in adrenal lesions to be as good as quantitative analysis, others have not supported this observation [11,48]. It has been suggested [73] that qualitative

analysis is advantageous because the observer can compensate subjectively for motion artifacts and variations in signal intensity across the image, better appreciate focal signal loss in the lesion, and avoid phase cancellation at fat-water interfaces. The studies that favored quantitative analysis, however, suggested that visual assessment can be difficult, unreliable, and less sensitive [11,48]. It is not unexpected that visual analysis may not be as accurate as quantitative analysis because the human eye may not be sensitive to minimal signal loss on OP imaging. Also, the different contrast display of the IP and OP images, and variability in scanner, sequence, and patientrelated parameters between the IP and OP acquisitions may introduce errors in the perceived signal intensity of the mass. With dual-echo GRE acquisitions, the IP and OP images are acquired simultaneously in a single breath-hold. Therefore, the slices are obtained in the same anatomical position regardless of the patient’s ability to hold his or her breath, eliminating the possibility of slice misregistration [55]. There is also no hardware and sequence-related variability between the two acquisitions, allowing the IP image to be used as the internal reference. With the use of this sequence, Namimoto and colleagues [55] were able to quantify the fat fraction in adrenal masses, albeit with some limitations. Despite the variability in the sequences used for imaging adrenal lesions, inconsistency of SGRE sequence parameters, and the various qualitative and quantitative image analyses methods used to assess signal loss in adrenal lesions, the results of the studies are highly accurate, indicating that the technique of CSI is robust and reliable. MR versus CT CT attenuation values have been a reliable means for characterizing adrenal masses. At or below a threshold value of 10 Hounsfield units (HU) on a nonenhanced CT, an adrenal lesion can be diagnosed confidently as an adenoma [77]. Korobkin and colleagues [7] found an inverse linear relationship between the percent of lipid-rich cortical cells in adrenal adenomas, unenhanced CT attenuation values, and relative changes in MR signal intensity on CSI by quantitative and qualitative analyses. It seems from this study that the lipid-rich clear cells, not the compact cells that contain less lipid, contribute to the low attenuation values and signal loss in adrenal adenomas. Outwater and colleagues [67] found a significant

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correlation between CT attenuation and chemical shift ratios values, and that both values were indeterminate in a similar subset of benign lesions (six lesions). Had the authors used an attenuation value of 10 HU instead of 17 HU to characterize adrenal adenomas on noncontrast CT, three of their adenomas (11–16 HU) would have fallen in the CT-indeterminate category. All three masses were characterized correctly as adenomas on CSI. Thus, this paper may have underestimated the true performance of chemical shift MR imaging. McNicholas and colleagues [78] attempted to develop an algorithm using CT and CSI for the characterization of adrenal masses in patients with a primary cancer and no other metastatic disease. Using a quantitative adrenal-spleen ratio of 70 or less for benign lesions, CSI correctly characterized 33 of 37 adrenal masses with attenuation values ranging from less than or equal to 0 HU to greater than 20 HU. The authors suggested an algorithm that uses the density reading on noncontrast CT as the first step for evaluating an adrenal mass, followed by CSI MR imaging for CT-indeterminate lesions (1–20 HU). Had the authors used an attenuation value of 10 or less instead of 0 HU for characterization of adenomas, however, four of five CT-indeterminate masses (0–10 HU) would have been classified correctly as definitely benign. Thus, this paper may have underestimated the performance of nonenhanced CT for characterization of adrenal adenomas. There is emerging evidence that chemical shift MR imaging is more sensitive for detecting lipid within adrenal masses than nonenhanced CT (Fig. 15). This could relate to improved MR techniques (sequences and coils) used in these studies compared with the older studies. In a new study by Israel and colleagues [79], 8 of 13 CTindeterminate adrenal masses (greater than 10 HU) were characterized definitively by CSI, using two quantitative analysis methods (see Table 1). The authors found qualitative analysis of signal loss to be inferior to quantitative analysis. Elias and colleagues [80], using ROC analysis, found CSI to be the best technique for distinguishing adenomas from nonadenoma compared with nonenhanced CT values and mass size. Haider and colleagues [81], in a study of 27 adrenal adenomas measuring over 10 HU, found the sensitivity and specificity of CSI for characterizing these lesions as adenomas to be 67% and 100%, respectively, using quantitative analysis (SII normalized to renal cortex and medulla). The sensitivity of CSI decreased as the HU measurements of the masses

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increased. The results of this study show a similar specificity but lower sensitivity of CSI compared with CT washout values (sensitivity 89%, specificity 95%) for the characterization of lipid-poor adrenal masses using a 60% threshold value for percentage enhancement washout [82]. These studies re-establish the role of CSI in characterizing CT-indeterminate adrenal masses, an important issue in view of increasing awareness of risks for ionizing radiation, especially in younger patients without malignancy.

Hyperfunctioning versus nonhyperfunctioning adenoma Mitchell and colleagues [25] suggested that hyperfunctioning adenomas may contain less lipid than nonfunctioning adenomas. Slapa and colleagues [65] confirmed this and found a significantly smaller amount of fat in hyperfunctioning compared with nonhyperfunctioning adenomas. Miyake and colleagues [83] reported that aldosterone-secreting adenomas had more lipid-rich cells than cortisol-producing adenomas. These observations were not confirmed in other studies [7,47,74,75], and no reliable imaging features have been identified to help distinguish adenomas based on their function. On histology, Korobkin and colleagues [7] did not find a significant difference between the mean percentage of lipid rich cells in 10 nonhyperfunctioning and 10 hyperfunctioning adenomas.

Gadolinium-enhanced MR imaging The results of gadolinium-enhanced MR imaging for the characterization of adrenal masses have been controversial but predominantly disappointing. The results of the initial studies by Krestin and colleagues [46,63] were promising. Mild enhancement and early washout (at 10 minutes) was seen in most adrenal adenomas after the administration of 0.1 mmol/kg of gadolinium; malignant tumors and pheochromocytoma showed strong enhancement and slower washout. The postulated pathophysiologic mechanism is based on the intense perfusion, disturbed permeability of capillaries, and the size of the extravascular extracellular space of malignant tumors, leading to increased diffusion and prolonged retention of contrast in the extravascular extracellular space [63,76]. Unfortunately, other authors could not reproduce these promising results [11,61,64,84], and the enhancement characteristics did not help to characterize adrenal

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Fig. 15. Small, incidentally discovered, left-adrenal adenoma (arrows) in a patient without known malignancy. (A) Axial nonenhanced CT, (B) coronal IP, and (C) coronal OP SGRE (155/4.4 and 2.2/70(). The mass measures 25 Hounsfield units on nonenhanced CT, indicating a lipid-poor lesion. Quantitative analysis (SII) of the signal intensity of the mass on MR imaging showed 49% signal loss (IP signal intensity 53; OP signal intensity 27; SII (IP-OP/IP)
100 = 49%) indicating a lipid-rich adenoma.

masses accurately, although some studies [65,66,76] found enhancement and washout patterns to be useful in equivocal cases. Thus, gadolinium-enhanced MR imaging for differentiation between adenomas and nonadenomas has fallen out of favor. The exact cause of ineffectiveness of gadolinium-enhanced washout curves is unknown. Although iodinated contrast and gadolinium chelates are nonspecific extracellular agents, the relationship between signal intensity changes and gadolinium concentration is not linear [85], as is the case with iodinated contrast agents. It is therefore possible that at clinically used doses, tissue gadolinium concentration at 1 and 15

minutes does not produce notable differences that can be used for characterization. Other benign conditions Cysts Adrenal cysts are extremely rare, occurring in 0.06% of autopsies [8]. They are found in asymptomatic adult patients, with a 3:1 female predilection [40]. Four types of adrenal cysts have been identified histologically: endothelialized cysts, pseudocysts, parasitic cysts, and epithelial cysts [40]. Endothelialized (or endothelial) cysts are the most common and account for 45% of all adrenal cysts [86–90]. Adrenal pseudocysts lack an

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Fig. 16. Small, right-adrenal cyst (arrows) in a patient with cirrhosis and portal hypertension. (A) IP and (B) OP SGRE (155/4.4 and 2.2/70(), (C) axial T2W fat-suppressed fast spin-echo image (5200/89), and (D) axial postgadolinium T1W three-dimensional SGRE with fat suppression image (5.2/1.2/12(). Note the uniform low signal intensity of the mass on T1W IP and high signal intensity on T2W imaging; similar to cerebrospinal fluid, lack of focal signal loss on the OP image, and no internal enhancement after gadolinium.

epithelial lining, and are the most likely to manifest clinically. They probably arise from prior episodes of hemorrhage into a normal or abnormal gland. Parasitic cysts (usually echinococcal) and epithelial cysts are less common [40,87]. The MR appearance of simple cysts may range from that of fluid in a simple cyst (homogeneous low T1 and high T2 signal intensity without wall enhancement) (Fig. 16) to a more complex appearance, usually seen with adrenal pseudocysts. These cysts may be large, have thick walls [35] and septations, and contain blood products, proteinaceous fluid, infectious debris, or soft-tissue components [91]. This will result in variable T1 and T2 signal intensity of the cyst content [3,91]. Occasionally cysts can be very large [35,90], and complex cysts may be difficult to differentiate from an abscess, necrotic tumor, or cystic pheochromocytoma [92]. Hemorrhage Adrenal hematomas result from traumatic and nontraumatic causes. Nontraumatic causes include stress associated with sepsis, especially meningococcal infection, burn, or hypotension; neonatal stress; coagulopathy; and underlying benign and malignant adrenal tumors [35,93].

Pheochromocytoma is the most common cause of massive bleeding from a primary adrenal tumor. Other tumors that may bleed include myelolipoma, hemangioma, and adrenocortical carcinoma. Hemorrhagic adrenal metastases and hemorrhage in adrenal adenomas are rare [93]. Many cases of adrenal hemorrhage are clinically silent, and usually resolve spontaneously; less commonly, hemorrhage liquefies and persists as a pseudocyst [3]. Approximately 80% of adrenal hemorrhages are unilateral, mostly on the right because of the direct drainage of the right adrenal vein into the inferior vena cava [3]. Left-side hemorrhage may result from left renal vein thrombosis [94]. Patients with coagulopathies are prone to bilateral hemorrhage [35,95,96]. Adrenal hematomas can occur in 2% of patients who suffered severe trauma, and in the right adrenal gland following liver transplantation [97–100]. MR imaging can be used to determine the age of the hematoma. In the subacute stage (7 days to 7 weeks after onset), hematomas are hyperintense on T1W and T2W images compared with liver. In the chronic stage (which typically begins 7 weeks after onset), a hypointense rim is present on T1W and T2W images because of hemosiderin deposition and the presence of a fibrous capsule. Hematoma may be multilocular, and each locule

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may have different signal-intensity characteristics because of different degrees of oxidation [101]. Gadolinium-enhanced MR imaging is necessary to determine whether blood is the sole component of the hematoma, a finding that likely indicates a benign cause. GRE imaging with longer TE values is helpful in demonstrating the magneticsusceptibility effect of ‘‘blooming,’’ which results from hemosiderin deposition, and can be used to monitor hemorrhage as it progresses from methemoglobin to hemosiderin [93]. Infection Granulomatous disease of the adrenal gland is the second–most common cause of adrenal insufficiency in the United States after idiopathic Addison disease [35,90,102]. Tuberculosis, histoplasmosis, and blastomycosis usually involve both adrenal glands, often asymmetrically [3]. The appearance of the adrenal glands in infections has not been described on MR imaging, but is described on CT as enlarged with central low attenuation, representing caseous necrosis and peripheral enhancement [31,103,104]. Acute adrenal abscess is a rare complication of adrenal hemorrhage in childhood [3], and AIDS with extrapulmonary Pneumocystis carinii infection [105]. Myelolipoma Myelolipoma is an uncommon benign lesion composed of mature adipose and proliferating hematopoietic tissue [106]. It is asymptomatic in most cases, but large tumors may cause discomfort or flank pain because of compression or hemorrhage [107]. An association with endocrine dysfunction has been reported, but this association is probably related to coexistence with adenoma [3,87,108].

Most adrenal myelolipomas are small (less than 5 cm), but giant forms weighing up to 5.5 kg have been reported [109] (Fig. 17). On MR imaging, myelolipomas are characterized by the presence of gross fat on all sequences [11,110]. The high signal intensity of the fat within myelolipoma on T1W and T2W images should resemble that of intra-abdominal fat [111]. The presence of fat should be confirmed on T1W sequences performed with frequency-selective fat-suppression pulses. Myelolipomas have heterogeneous signal intensity on T2W imaging because of the nonuniform admixture of fat and bone marrow components [93]. These lesions enhance after gadolinium administration because the myeloid portion is vascular [35]. Although there is almost always a region of definite fat on MRI, myelolipomas occasionally have predominantly myeloid components [35,112]. Coexistence of gross fat and areas of microscopic lipid (demonstrated by signal loss on OP imaging) in myelolipomas has been reported [93]. Hemorrhage is seen most frequently in men, and can occur in large myelolipomas [107]. As for differential diagnosis, lipoma and liposarcoma must be considered for a mass with significant lipid content, but an adrenal location of liposarcomas is rare [87]. Hemorrhagic adrenal adenoma, adrenocortical carcinoma, and adenocarcinoma metastatic to the adrenal gland also may simulate myelolipoma [113,114].

Hemangioma Hemangiomas of the adrenal gland are extremely uncommon [87]. Adrenal hemangiomas vary from 2 to 22 cm in size, are generally asymptomatic, and symptoms are usually related

Fig. 17. Giant left-adrenal myelolipoma with hemorrhage. (A) Axial T1W spin-echo (500/20), and (B) axial fat suppressed T2W fast spin-echo (5100/90). The fat within the mass has similar signal intensity to the intra-abdominal fat, and suppresses with frequency-selective fat saturation. Note the marked heterogeneity of the mass, which was surgically removed.

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to the size of the tumor. Adrenal hemangiomas are cavernous and rarely capillary [40,115]. Hemangiomas have low signal intensity on T1W, and high signal intensity on T2W images compared with liver. Central T1 hyperintensity and T2 hypointensity are caused by hemorrhage. The enhancement pattern is similar to that of liver hemangiomas [35,40,116–118]. This pattern of enhancement also has been reported in two cases of malignant hemangioblastoma [119]. If the diagnosis of hemangioma is suggested on imaging, surgical resection of the lesion is recommended, especially if large, because of the risk for hemorrhage and inability to exclude carcinoma [40,87]. Nonmetastatic enlargement of the adrenal gland Diffuse enlargement of the adrenal glands in patients with extra-adrenal malignancy has been reported [120,121]. It is believed to be caused by adrenal hyperplasia rather than metastatic neoplasm, and that there is disturbed pituitaryadrenal regulation [121]. Malignant neoplasms Metastasis The adrenal gland is the fourth–most common site of metastatic disease in the body after the lung, liver, and bone. The primary tumors most often involved are lung, breast, thyroid, colon, and melanoma [122,123]. Because of the high rate of occurrence of clinically silent adrenal adenomas, many adrenal masses are benign, even in patients with known malignancy [59,124]. Adrenal metastases can present as round or oval soft tissue masses, or diffuse adrenal enlargement. Metastases tend to be larger than adenomas, infiltrating and less well defined, and heterogeneous. Small metastases can be homogeneous and well defined [8,35]. On MR imaging, metastases typically have hypointense signal intensity on T1W, and hyperintense signal intensity on T2W images relative to liver [3]. Some metastases have iso- or hypointense T2 signal [125,126] or are markedly hyperintense on T2W imaging, mimicking pheochromocytoma [3]. Most metastases do not show signal loss on OP imaging, but occasionally they can contain intracellular lipid, such as metastases from clear-cell and granularcell renal-cell carcinoma [127–133]. Accurate characterization of an adrenal lesion may not be critical if the gland is one of many sites of metastasis, but if the adrenal gland is the only possible site of metastasis, precise characterization is crucial for management [40]. Using CSI,

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Schwartz and colleagues [132] characterized adrenal masses and avoided adrenal biopsies in 54% of their patients with known malignancies and adrenal masses. Lymphoma Primary adrenal lymphoma is uncommon, and typically occurs in association with other sites of retroperitoneal involvement [3,35]. Adrenal involvement usually is seen with the non-Hodgkin’s more than the Hodgkin’s histologic type [40,134,135]. Early involvement may not be apparent or may result in diffuse adrenal enlargement with the shape of the adrenal gland maintained; late disease demonstrates nodular enlargement [136]. The MR appearance of lymphoma is nonspecific and the adrenal gland/mass appears hypointense relative to liver on T1W imaging, heterogeneously hyperintense on T2W imaging, and does not show signal drop on OP imaging [11]. The diagnosis of adrenal lymphoma usually is made because most patients have an established diagnosis of lymphoma at time of imaging [40]. Primary adrenal non-Hodgkin’s lymphoma presents as large adrenal masses that tend to be cystic and heterogeneous. Adrenal insufficiency is seen in two thirds of cases with bilateral involvement, and is the most common cause of adrenal insufficiency resulting from malignant invasion [86,137,138]. Collision tumors Collision tumor refers to independently coexisting neoplasms without significant tissue admixture [87]. Both tumors may be malignant or benign, or one may be benign and the other malignant [87,139]. Adrenal collision tumors are extremely rare [139]. They should be suspected on MR imaging when there is only focal signal intensity drop in an adrenal mass on OP images [133,139], although this appearance may be seen occasionally in adrenal adenomas (Fig. 14). Contiguous adrenal adenoma and metastasis [139], adenoma and hemorrhagic cyst [133], adenoma and myelolipoma [87,140,141], and adenoma and pheochromocytoma [142] have been reported.

Rare adrenal tumors The features of several rare benign and malignant adrenal tumors have been described on MR imaging. These tumors include adrenal angiosarcoma [87], primary malignant melanoma [87], extramedullary hematopoiesis [143], adenomatoid

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tumor [144], and bilateral cystic lymphangiomas associated with nevoid basal-cell carcinoma syndrome [145]. Many of the described MR imaging features are nonspecific. Malignant tumors are large and show central hemorrhage or necrosis; benign tumors are cystic, solid, or both. None of these tumors demonstrated signal loss on OP imaging. Although the MR imaging features of these lesions are nonspecific, they are not features of benign lesions, and surgical resection is recommended. Hypoadrenalism Approximately 90% of the adrenal cortex must be destroyed before the onset of primary adrenal insufficiency or Addison disease [3]. Hypoadrenalism usually is a result of primary idiopathic atrophy caused by autoimmune disease [146] and the adrenal glands become small and difficult to detect [3]. Hypoadrenalism can be secondary to chronic granulomatous disease, hemorrhage, amyloid, sarcoid, metastatic disease, hemochromatosis, fungal infection, AIDS, and antiphospholipid syndrome [147–150], and the glands can be enlarged, normal, or atrophic in these conditions [151]. Technical considerations and recommendations When imaging adrenal masses, a torso-phased array coil is preferred to the body coil to maximize the SNR. It is important to minimize variations between the IP and OP sequences (same sequence parameters except for the TE value, no autoretuning of the scanner, same breath-hold), so that chemical shift imparts the only difference between the IP and OP images. The shortest possible TE for OP imaging should be used to minimize the T2*-induced signal intensity loss. Thus, a dual-echo sequence that acquires simultaneous images at the earliest (OP) and (IP) TEs is the ideal sequence to use for this purpose. The authors suggest the following protocol and analysis methods for routine clinical practice: 1. Axial and coronal dual-echo SGRE sequence (TR 100–200, TE 2.3 and 4.5, flip angle 70(). The slice thickness should not exceed 5 mm for small masses, without a gap. If separate IP and OP acquisitions are used, only the TE value should change between the two acquisitions. 2. Axial T2W fast SE with respiratory triggering, for characterization of pheochromocyto-

mas and other adrenal tumors, and detection of liver metastases. 3. Coronal dynamic gadolinium-enhanced three-dimensional SGRE sequence acquired in the arterial and venous phases after gadolinium. This sequence is most useful for evaluation of malignant tumors (organ of origin, vascular invasion). 4. If the dual-echo gradient-echo sequence is used, evaluation for the presence of signal loss in an adrenal lesion on OP imaging can be performed by simple visual inspection of the signal intensity of the mass relative to the spleen on IP and OP images, or by comparing the IP and OP images to one another, after fixing the contrast window width and level. Visual analysis should be followed by a quantitative analysis of the signal intensity of the mass on OP and IP; either the SII or the adrenal-spleen ratio calculations. Although universal thresholds to characterize adenomas have not been established, the most recent studies suggest a value of greater than 16.5% for the SII, and less than 0.71 for the adrenal-spleen ratio [63,75,79] for characterization of adenomas. If the IP and OP images are performed as separate acquisitions, it is preferable to use an internal reference (spleen or liver) for qualitative and quantitative analyses, after excluding hepatic steatosis, and iron deposition in liver and spleen.

Summary Most incidentally discovered adrenal masses are cortical adenomas, even in patients with underlying malignancy. Some adrenal masses have pathognomonic features on MR imaging, such as simple cysts and myelolipomas, and others have nonspecific features of benign or malignant lesions. Most incidentalomas have nonspecific morphologic features. Most adenomas contain intracellular lipid and can be diagnosed correctly on SGRE IP/OP imaging, but some are lipid-poor and cannot be characterized accurately. Most adrenal nodules that measure less than 3 cm in diameter are benign [113]. In the absence of history of malignancy, a small homogeneous lipid containing incidentally discovered mass can be left alone and does not require further investigation. If the mass is lipid-poor, then correlation with hormonal function and 6-month to 1-year imaging follow-up to assess for ‘‘stability’’ is adequate.

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If the mass is larger than 3 cm or has heterogeneous internal signal, however, then correlation with hormonal studies and further evaluation with biopsy may be necessary. Likewise, in the case of a mass that cannot be characterized definitely as an adenoma in a patient with underlying malignancy, or if a lipid-containing adrenal mass is detected in the presence of a primary tumor that may contain lipid, such as clear-cell renal-cell carcinoma, biopsy may be necessary. The role of MR imaging in the presence of adrenal cortical or medullary hyperfunction is to identify the adrenal or extra-adrenal source, and determine if surgery is the appropriate treatment. MR imaging also plays a key role in determining the origin of large retroperitoneal masses and staging malignant adrenal tumors.

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