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Adrenal Imaging and Intervention
Brian C. Allen, MDa,*, Isaac R. Francis, MBBSb
KEYWORDS
. Adrenal adenoma . Adrenocortical carcinoma . Pheochromocytoma
· Absolute percentage washout . Relative percentage washout . Cushing syndrome
· Conn syndrome
KEY POINTS
· Incidental adrenal masses are common and most are benign.
· Imaging appearances suspicious for malignancy include large size (>4 cm), growth, heterogeneity, irregular margins, and necrosis.
· Adrenal masses may be biochemically active and produce excess glucocorticoids, aldosterone, androgens, and/or catecholamines.
· Computed tomography can differentiate most adenomas and nonadenomas using absolute or rela- tive percentage washout, because adenomas tend to enhance earlier and stronger, and deenhance earlier and to a greater degree than do most nonadenomas.
INTRODUCTION
The adrenal glands are complex endocrine organs composed of 2 distinct regions: the adrenal cortex and the adrenal medulla. The cortex is composed of 3 zones: the outer zona glomerulosa, which is the site of aldosterone production; the middle zona fasciculata, which is the site of cortisol and sex steroid production; and the inner zona reticu- laris, which secretes cortisol, androgens, and es- trogens, and is the source of cholesterols for steroidogenesis. The adrenal medulla is the cen- tral aspect of the gland and primarily secretes catecholamines.1
The adrenal glands are a common site for benign and malignant primary tumors as well as metastatic disease. Cross-sectional imaging al- lows both the detection and characterization of many adrenal masses, making percutaneous bi- opsy unnecessary in many cases.
This article reviews imaging protocols for adre- nal imaging, including computed tomography (CT), MR imaging, and fluorine-18 fluorodeoxyglu- cose (FDG) PET/CT. Diagnostic algorithms are described for the imaging evaluation of incidentally detected adrenal masses, the noninvasive detec- tion of adrenal tumors in patients with known biochemical abnormalities, and staging of patients with known primary malignancies. In addition, imaging-guided interventions for the diagnosis and therapy for various adrenal tumors are discussed.
NORMAL ANATOMY
The normal adrenal glands are inverted Y-shaped or V-shaped organs in the suprarenal space, en- closed by the Gerota fascia. The adrenal glands have straight or concave margins with bodies measuring less than 10 to 12 mm in length and
Disclosure: The authors have nothing to disclose.
ª Abdominal Imaging, Department of Radiology, Duke University Medical Center, 2301 Erwin Road, Box 3808, Durham, NC 27710, USA; b Abdominal Imaging, Department of Radiology, University of Michigan Hospitals, 1500 East Medical Center Drive, Room BID540, Ann Arbor, MI 48109-5030, USA
* Corresponding author.
E-mail address: brian.allen@duke.edu
limbs measuring less than 5 to 6 mm in thickness.2 There are usually 3 adrenal arteries, arising most commonly from the inferior phrenic artery, the aorta, and the renal artery. There are usually single adrenal veins. The right adrenal vein drains directly into the inferior vena cava and the left adrenal vein drains into the inferior phrenic vein and then the renal vein. Vascular anatomy is difficult to identify on routine cross-sectional imaging, and is occa- sionally identified during CT angiography, but is extremely important for intravascular catheter- based diagnostic and interventional techniques.
On CT, the normal adrenal glands are symmetric and of homogeneous soft tissue density. On MR imaging, the adrenal glands are of intermediate signal intensity on T1-weighted (T1w) imaging, and are isointense to slightly hypointense to liver on T2-weighted (T2w) imaging.3 There is a wide range of normal uptake in the adrenal glands on FDG-PET, from no uptake to moderate uptake.4 In general, the uptake within the adrenal glands on FDG-PET is similar to or less than background liver.
IMAGING PROTOCOLS
The imaging evaluation of known or suspected ad- renal abnormalities typically consists of CT, MR imaging, or PET/CT. Metaiodobenzyl-guanidine (MIBG; preferred) and, less commonly, octreotide scintigraphy may be used to identify pheochromo- cytomas, but these targeted nuclear medicine studies should be used selectively in patients with a high pretest probability of disease (eg, patients with a family history, patients with an associated hereditary disorder, patients with biochemical evidence of excess sympathetic hormones).5
CT imaging of the adrenal glands typically con- sists of a multiphase study including an unen- hanced scan, a 1-minute delayed-enhanced scan, and a 15-minute delayed-enhanced scan (Box 1). The unenhanced scan is used to identify lipid-rich adenomas, which can be diagnosed when an adrenal nodule is homogeneous and measures less than 10 Hounsfield units (HU). If a mass can be characterized as a lipid-rich ade- noma on the unenhanced scan, intravenous contrast is not required. For adrenal masses that are homogeneous and measure greater than 10 HU in a patient with suspected metastasis, intravenous contrast administration and washout calculations are necessary. The unenhanced, 1-minute, and 15-minute scans are used to calcu- late absolute percentage washout (APW) and/or relative percentage washout (RPW) in order to differentiate lipid-poor adenomas from metasta- ses. Details of how to perform these calculations and the formulae used are described later.
MR imaging of the adrenal glands is generally performed with a phased-array body coil with the patient supine (see Box 1). A typical adrenal proto- col begins with a coronal localizer using a fast sequence such as single-shot turbo spin echo/ single-shot fast spin echo (ssFSE), which provides an anatomic overview of the abdomen. Gradient dual-echo T1w (in-phase and opposed-phase) imaging with the longer echo time assigned to the in-phase echo is fundamental in adrenal nodule evaluation. In-phase and opposed-phase imaging allow detection of intravoxel lipid within adrenal masses, manifesting as nonlinear signal loss on the opposed-phase images. The presence of macroscopic fat within an adrenal mass can be seen on opposed-phase images by the character- istic India ink artifact at fat-water interfaces. Axial
Box 1 Simplified imaging protocols
CT imaging protocol
Unenhanced CT to identify lipid-rich adenomas (<10 Hounsfield units [HU])
One-minute and 15-minute delayed-enhanced CT to differentiate lipid-poor adenomas from metastases using absolute percentage washout (APW) or relative percentage washout (RPW)
MR imaging protocol
Coronal and axial T2w single-shot fast spin echo localizer
Axial and coronal T1w dual-echo gradient echo to assess for lipid in lipid-rich adenomas and India ink artifact in myelolipomas
Fat-suppressed T2w fast spin echo to assess for pseudocysts, cysts, and the occasional light-bulb-bright pheochromocytoma
(Optional) Fat-suppressed T1w gradient echo before and dynamically after intravenous contrast mate- rial to assess for venous thrombus in patients with suspected adrenocortical carcinoma
fat-suppressed T2w images are useful to evaluate for the typical marked hyperintensity of cysts and pseudocysts, and the so-called lightbulb-bright sign of some pheochromocytomas. Multiphase contrast-enhanced imaging is sometimes performed using a three-dimensional (3D), fat- suppressed T1w gradient echo sequence; how- ever, the contrast washout-based calculations used with CT are not accepted or widely used for MR imaging because of the non-normalized units of signal intensity. For this reason, many MR adrenal mass protocols forgo the use of contrast-enhanced imaging for adrenal nodule characterization. In patients with dominant adrenal masses suspicious for adrenocortical carcinoma, contrast-enhanced imaging is helpful to determine whether there is vascular invasion.
FDG-PET/CT typically is used as a staging ex- amination in patients with certain known primary malignancies. Qualitative visual assessment of radiotracer uptake compared with background liver activity and quantitative analysis using stan- dardized uptake values (SUV) are the methods used to determine whether a lesion is suspicious for a malignancy.6 Adrenal nodules with uptake greater than background liver are likely malignant, adrenal nodules with uptake less than background liver are likely benign, and adrenal nodules with uptake similar to background liver are equivocal. FDG-PET/CT can also be used for the detection of distant metastatic disease in patients with prob- able malignancy.
IMAGING FINDINGS/PATHOLOGY Incidental Adrenal Masses
Incidental adrenal masses (ie, adrenal masses measuring >1 cm that are discovered on an imag- ing study performed for an indication other than for the adrenal gland) are common, occurring in up to 7% of adults, and are often referred to as inciden- talomas.7 Most incidentally discovered adrenal masses are benign, and the most commonly discovered incidental adrenal mass is a nonhyper- functioning adenoma.8 The purpose of diagnostic imaging is to differentiate benign masses from those that may require treatment. Benign, so-called leave-alone, masses include nonhyper- functioning adenomas, myelolipomas, cysts, pseudocysts, and unclassified lesions with long- term stability (Box 2).
Benign lesions with specific imaging findings Myelolipoma Myelolipomas are benign adrenal masses composed of variable amounts of fat, myeloid cells, and erythroid cells. Their imaging appearance is characteristic, with the
Box 2 Simplified differential diagnosis
Benign
Adenoma
Pseudocyst
Hemorrhage Myelolipoma
Cyst Pheochromocytoma Granulomatous disease
Malignant Metastasis Adrenocortical carcinoma
Pheochromocytoma
identification of macroscopic fat within an adrenal mass (Box 3). On CT imaging, macroscopic fat, similar in attenuation to the adjacent retroperito- neal fat, is seen on both unenhanced and intrave- nous contrast-enhanced examinations (Fig. 1). In general, unenhanced CT is more sensitive for the diagnosis of macroscopic fat than is contrast- enhanced CT because of pseudoenhancement ef- fects. On MR imaging, the fat component of a myelolipoma is hyperintense on T1w images without fat suppression and becomes hypointense on T1w images with fat suppression. A similar change in signal is seen on T2w imaging (hyperin- tense on T2w imaging without fat suppression,
Box 3 Diagnostic criteria for adrenal masses
Less than 10 HU and homogeneous on unen- hanced CT is diagnostic of a lipid-rich adenoma APW greater than 60% and RPW greater than 40% are suggestive of lipid-poor adenoma
Nonlinear signal loss within an adrenal nodule on opposed-phase imaging is suggestive of a lipid-rich adenoma
Large quantities of macroscopic fat (India ink artifact) within an adrenal mass are diagnostic of myelolipoma
Adrenal cysts (rare) and adrenal pseudocysts (uncommon) are of fluid density or signal inten- sity and do not enhance
Malignant adrenal masses tend to be large (>4 cm) and heterogeneous with central necro- sis and irregular margins
hypointense on T2w imaging with fat suppression). On T1w opposed-phase images, a characteristic India ink artifact is seen at the fat-water interfaces of the mass. This artifact is diagnostic of the pres- ence of macroscopic fat and characteristic of myelolipoma (Fig. 2). Myelolipomas are occasion- ally complicated by calcifications and hemor- rhage, but necrosis is rare.2 Some adrenocortical cancers can contain small quantities of macro- scopic fat (generally <10% of the total volume).
Cyst True cysts of the adrenal gland are rare, benign, homogeneous, and do not enhance
following intravenous contrast administration (Fig. 3). On CT, they measure water density (<20 HU); on MR imaging, they are fluid signal intensity. Occasionally, an internal septation or peripheral calcification is seen. Complicated cysts may have areas of apparent wall thickening or irregular- ity that generally do not enhance. The presence of nodular or thick septal enhancement within a cystic adrenal mass is an indication for resection.
Other adrenal lesions
Adrenal hemorrhage and pseudocysts Adrenal hemorrhage is often asymptomatic, but patients may present with flank pain. Bilateral adrenal hemorrhage may present as a life-threatening condition with high mortality related to the un- derlying disease and superimposed endocrine dysfunction.º Causes of adrenal hemorrhage include anticoagulation (ie, supratherapeutic treat- ment), septicemia (ie, classically related to meningococcus [Waterhouse-Friderichsen syn- drome]), iatrogenic events (eg, adrenal biopsy, ipsilateral partial nephrectomy), trauma, and spontaneous hemorrhage of an underlying adrenal tumor (rare).
On imaging, the appearance of adrenal hemor- rhage depends on the time of imaging following the event. On CT, acute and subacute adrenal hemorrhage may appear as a round or oval high- attenuation mass that does not enhance following intravenous contrast administration. Hemorrhage may also present as an infiltrative/amorphous mass, or as adreniform enlargement that should decrease in size over time.9
The MR appearance of adrenal hemorrhage de- pends on the age of the blood products and the
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relative amount of deoxyhemoglobin, methemo- globin, and hemosiderin.1º Subacute hemorrhage is usually heterogeneously hyperintense on T1w imaging because of methemoglobin.
Chronic hemorrhage usually manifests as either dense calcification or a pseudocyst. Pseudocysts are fluid signal intensity centrally with peripheral calcifications or hemosiderin (hypointense on T2w imaging). Occasionally, a thin peripheral enhancing rim can be seen.
Granulomatous disease In the acute phase, gran- ulomatous disease can manifest as no abnormality (common) or bilateral adrenal nodules (rare). In the chronic phase, granulomatous disease can show no abnormality (common) or bilateral calcifications (common).
Malignant lesions
Imaging appearances suspicious for adrenal malignancy (metastases, adrenocortical carci- noma, malignant pheochromocytoma) include new or enlarging enhancing adrenal masses without history of intercurrent severe atypical infection, large size (>4 cm), heterogeneity, irreg- ular margins, and necrosis (see Box 3). Patients with these imaging characteristics require evalua- tion with biochemical studies, biopsy, and/or resection. Note that suspected adrenocortical cancer should not be biopsied to avoid the risk of tumor spillage.
In patients who have one or more adrenal nod- ules without suspicious imaging features but who have a suspicious history (eg, personal history of malignancy, concern for metastatic disease), further imaging with adrenal protocol CT, adrenal protocol MR, and/or FDG-PET/CT can help differ- entiate adenoma from metastasis.
American College of Radiology Incidental Findings Committee: management recommendations
Incidental adrenal masses are adrenal masses measuring greater than 1 cm that are discovered on cross-sectional imaging performed for an indi- cation other than the evaluation of the adrenal glands (Fig. 4). The American College of Radiology (ACR) has devised a flow chart for the evaluation of incidentally discovered adrenal masses.7 If an ad- renal mass can be characterized definitively as a benign lesion (eg, cyst, pseudocyst, calcification, myelolipoma) then no further work-up is required. If a homogeneous adrenal mass measures 1 to 4 cm and shows a density of less than 10 HU on unenhanced CT or nonlinear generalized signal loss on opposed-phase MR imaging, a lipid-rich adenoma may be diagnosed in most situations. Exceptions on MR imaging include patients with known clear cell renal cell carcinoma or hepatocel- lular carcinoma because such metastases can appear identical. Some adrenocortical cancers can contain lipid, but are not homogeneous. If an adrenal mass is unchanged for longer than 1 year, it is likely to be benign but may or may not be functional (eg, hyperfunctioning adenoma, benign pheochromocytoma).
In patients with an indeterminate adrenal mass, a personal history of cancer, and no prior imaging that can be used to assess stability of the adrenal mass, further evaluation should be considered with CT, MR imaging, or FDG-PET/CT. If a mass cannot be characterized as an adenoma; if it is enlarging; or if it has other suspicious features of malignancy, such as heterogeneity, margin irregu- larity, or internal necrosis, percutaneous biopsy may be indicated; particularly if the adrenal gland is the only site of potential metastasis.
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In general, the primary role of adrenal protocol CT and adrenal protocol MR is for the differentia- tion of adenoma from metastasis in at-risk pa- tients. It should not be performed in all patients with an incidental adrenal nodule; it is not capable of predicting adrenal mass hyperfunction; and it is not helpful in further characterizing heteroge- neous, necrotic, large (>4 cm), or otherwise complicated adrenal masses.
BIOCHEMICALLY ACTIVE ADRENAL MASSES
Biochemically active adrenal masses may arise from the adrenal cortex or adrenal medulla. Cortical tumors produce excess glucocorticoids, aldosterone, or androgens, and medullary tumors produce excess catecholamines.
Cushing Syndrome
Excess production of cortisol leads to the charac- teristic signs and symptoms of Cushing syndrome, including obesity, insulin resistance, depression, and hypertension. Hypercortisolism may be sub- clinical in about 5% of cases.11 Most cases of Cushing syndrome are caused by stimulation of the adrenal by a pituitary adenoma that secretes excess adrenocorticotropic hormone (ACTH). Pri- mary adrenal tumors (eg, adenoma, adrenocor- tical carcinoma) are the cause in about 20% of cases and ectopic ACTH production (ie, extrapitui- tary) is seen in approximately 1% of cases. The evaluation of patients with Cushing syndrome be- gins with biochemical testing and pituitary MR im- aging. If a pituitary adenoma is not detected, adrenal CT or MR imaging is performed next. If
both pituitary and adrenal causes are excluded, then a CT of the chest, abdomen, and pelvis is per- formed to identify an ectopic source. Biochemical tests include 24-hour urine free cortisol, late-night salivary cortisol test, and overnight dexametha- sone suppression test. 11
Conn Syndrome
Conn syndrome results from increased aldoste- rone level, which leads to sodium retention, hyper- tension, and potassium wasting. Clinically, the diagnosis is suspected in patients with hyperten- sion and hypokalemia, and is then confirmed by measuring serum aldosterone to renin levels.11 Conn syndrome may result from an adrenal cortical tumor or adrenal hyperplasia. Thin- section CT (slice thickness 2-3 mm) is the first imaging test used in patients with primary hyperal- dosteronism. Its purpose is to help subtype the disease and to exclude the possibility of a hyper- functioning adrenocortical cancer. Multiphasic im- aging with 15-minute delays is usually not necessary because the clinical suspicion is typi- cally unrelated to metastatic disease, and washout calculations are not designed to discriminate be- tween primary adrenal masses.
Because of the high prevalence of incidental nonhyperfunctioning adrenal nodules and the insensitivity of CT to small (<1 cm) adrenal nod- ules,12 the usefulness of CT for localizing the source of hyperfunction is limited, particularly in patients more than 40 years of age, who are more likely to have an unrelated adrenal nodule. Therefore, in patients greater than or equal to 40 years old with primary hyperaldosteronism
who desire a surgical cure, adrenal venous sam- pling by an experienced radiologist is required to localize the sites of aldosterone production. If the source is unilateral, then ipsilateral adrenalectomy is usually curative. If the source is bilateral (eg, ad- renal hyperplasia), then the management is usually medical (eg, spironolactone).
Pheochromocytoma
Pheochromocytomas are neuroendocrine tumors that arise from the chromaffin cells of the adrenal medulla and lead to excess catecholamine produc- tion. The excess catecholamines may cause head- ache, hypertension, diaphoresis, tachycardia, and anxiety. Pheochromocytomas are associated with multiple syndromes, including multiple endocrine neoplasia 2A and 2B, von Hippel-Lindau, neurofi- bromatosis 1, and the Carney triad. 13 Mutations in the succinate dehydrogenase gene complex also predispose patients to the development of heredi- tary pheochromocytomas. 14
The biochemical work-up for suspected pheo- chromocytoma consists of plasma metanephrines and urinary metanephrines, which have a com- bined sensitivity of 97% to 99%. 15
Most (90%) pheochromocytomas arise from the adrenal gland and most (90%) are benign. Approx- imately 10% are extra-adrenal (ie, paraganglioma) and approximately 10% are malignant. On CT
imaging, pheochromocytomas have a variable appearance but tend to be hypervascular, with avid arterial-phase enhancement.16 Rarely (<1%), pheochromocytomas mimic lipid-rich adenomas by measuring less than 10 HU on unenhanced CT (Box 4).17 In addition, although most (~75%) pheochromocytomas show slow washout of less than 60% APW and less than 40% RPW, a sub- stantial minority (~25%) mimic the washout pat- terns of lipid-poor adenomas. 18
On MR imaging, most pheochromocytomas are hyperintense on T2w imaging, but a substantial minority are not (Fig. 5). 19 Classically, pheochromo- cytoma has been described as light-bulb bright on T2w imaging, but this is not always the case. Pheo- chromocytomas tend to be heterogeneous and may show flow voids on T2w imaging, giving them a salt- and-pepper appearance. Following contrast admin- istration, pheochromocytomas avidly enhance. 13
MIBG scintigraphy is a nuclear medicine examination that has been used to localize pheo- chromocytomas and has both high sensitivity (95%-100%) and high specificity (100%).20 MIBG scintigraphy should be used in certain patient pop- ulations, such as those with relevant family history or hereditary disorders, and in those patients with positive biochemical markers but negative CT or MR imaging.5 It has also been used in the detec- tion of distant metastatic disease in patients with malignant pheochromocytomas. Although most
Box 4 Pearls and pitfalls
Pearls:
A homogeneous adrenal nodule that is less than 10 HU on unenhanced CT is diagnostic of a lipid-rich adenoma.
If an adrenal mass measures greater than 30 HU on unenhanced CT, adrenal CT with washout may be a better option than MR imaging with chemical shift imaging.
Pheochromocytoma may mimic adrenal adenoma. Biopsy of pheochromocytoma can be avoided by ob- taining preprocedural biochemical studies.
Malignant adrenal tumors and metastases tend to be large (>4 cm) and heterogeneous with central ne- crosis and irregular margins.
Pitfalls:
Some (~25%) pheochromocytomas show APW greater than 60% and could be confused with adenoma. Adrenocortical carcinoma, pheochromocytoma, clear cell renal cell carcinoma, and hepatocellular car- cinoma metastases may contain intravoxel lipid and may show heterogeneous signal loss on opposed-phase imaging.
Collision tumors (ie, metastatic disease to the adrenal gland with a coexisting benign lesion) are rare, but when present, 2 distinct regions of varying signal intensity within the same adrenal mass are gener- ally seen.
Biopsy of a suspected adrenocortical carcinoma is contraindicated because of the risk of tumor spillage and needle-track seeding. Such masses should move directly to open resection.
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pheochromocytomas are avid on PET/CT, MIBG scintigraphy is superior for the detection of pheo- chromocytomas, particularly those that are benign.20 In cases in which there is biochemical evidence of pheochromocytoma but negative MIBG imaging, octreotide scanning can be used as an alternative, but it is not a first-line test.
Operative resection is the primary treatment of pheochromocytoma. Recently, transarterial embo- lization and percutaneous thermal ablation have been used to treat pheochromocytoma, particu- larly in poor operative candidates.21,22 In patients undergoing local therapy or local tissue sampling (rare) of a suspected pheochromocytoma, alpha blockade is recommended in advance to avoid an adrenergic crisis. Iodine-131 MIBG therapy may be used for systemic treatment of select patients with metastatic pheochromocytoma.23
Adrenocortical Carcinoma
Adrenocortical carcinoma is a rare malignancy with an incidence of 1 to 2 per million people per
year. Most cases are sporadic, but there is an as- sociation with Li-Fraumeni cancer syndrome, Carney complex, Beckwith-Wiedemann syn- drome, familial adenomatous polyposis coli and multiple endocrine neoplasia type 1.24 There is a slight female predilection and a bimodal age distri- bution, with tumors seen in infants and children less than 5 years old, and in older patients in the fourth to fifth decades of life. Adrenocortical carci- noma is a functional (hormone-producing) tumor in 60% of cases, although this is less common in adults. The tumors may secrete androgens, cortisol, estrogens, or aldosterone, which can lead to Cushing syndrome, virilization, or feminiza- tion.24 In adults, adrenocortical carcinoma often presents as a large mass that is sometimes palpable, and with abdominal or flank pain. Thirty percent of patients present with metastatic dis- ease to regional and para-aortic lymph nodes, lung, liver, and bones.24
On CT, adrenocortical carcinomas tend to be large, usually measuring greater than 4 cm. In addition, tumor margins tend to be irregular, and
central necrosis and hemorrhage are common, particularly when the tumor is larger than 6 cm.25 Calcification may be seen in up to 30% of these tumors.25 Some adrenocortical cancers contain lipid and small quantities of fat. Adrenocortical carcinoma generally enhances heterogeneously following the intravenous administration of contrast. There may be local invasion of adjacent structures, and venous extension is common. Hussain and colleagues26 found size greater than 4 cm and heterogeneous enhancement to be the most important imaging factors for the character- ization of adrenocortical carcinoma. Adrenocor- tical carcinoma generally has APW and RPW values of less than 60% and 40%, respectively, compatible with nonadenomas.27
On MR imaging, adrenocortical carcinoma is het- erogeneously isointense to slightly hypointense to liver on T1w imaging, but is hyperintense if hemor- rhage is present. These masses are heterogeneous and hyperintense on T2w imaging (Fig. 6). On opposed-phase imaging, regions of heterogeneous signal loss representing intravoxel lipid or small re- gions (<10% total volume) of India ink artifact repre- senting macroscopic fat may be seen (see Box 4).28 Adrenocortical carcinoma shows avid, heteroge- neous enhancement with slow washout.29 In gen- eral, washout calculations are not performed for, or helpful in, the evaluation of adrenocortical carci- noma because of their size and heterogeneity.
FDG-PET/CT has a high sensitivity and high specificity for malignant adrenal masses, including adrenocortical carcinoma, with a sensitivity of up to 100% and a specificity of 88% to 97%. It is also used for the detection of distant metastatic disease.30,31
Surgery is the optimal treatment of adreno- cortical carcinoma and may be performed even with tumor thrombus extending to the right heart.
Transarterial embolization can be used for onco- logic palliation, pain relief, hormone suppression, and to decrease tumor bulk and vascularity before surgical resection.32 Percutaneous ablation in pa- tients who are poor operative candidates or with unresectable tumors has been shown to be effec- tive for short-term local control, particularly for small tumors, but long-term data are not avail- able.33 Percutaneous biopsy of a suspected adre- nocortical carcinoma in a surgical candidate is not advised because it can result in tumor spillage that renders the patient incurable.
ADRENAL MASSES IN THE SETTING OF KNOWN PRIMARY MALIGNANCY Computed Tomography
The adrenal glands are a common site for benign adenoma formation (2%-5% of patients) and met- astatic disease development. In the setting of known primary malignancy, differentiating ade- noma from metastasis is important because the diagnosis of adrenal metastasis can change the clinical stage and treatment plan.
However, up to 70% of adrenal adenomas contain intracellular lipid (cholesterol, fatty acids, and neutral fat), which reduces the unenhanced CT density of adenomas to less than that of other soft tissue nodules like metastases.34 A meta- analysis has shown that a threshold of 10 HU or less, which is the most widely used threshold, has a sensitivity of 71% and a specificity of 98% for the diagnosis of lipid-rich adenoma (see Box 3, Fig. 7).35
However, 10% to 40% of adenomas are lipid- poor and measure greater than 10 HU on unen- hanced CT.35 Lipid-poor adenomas may be characterized by adrenal washout calculations us- ing 1-minute delayed-enhanced and 15-minute
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delayed-enhanced CT imaging, because ade- nomas (both lipid rich and lipid poor) show earlier and more rapid washout than do metastases (Figs. 8 and 9).36 APW and RPW may be used to characterize these lipid-poor adenomas. APW is calculated as (1-minute HU - 15-minute HU)/ (1-minute HU - unenhanced HU) x 100. RPW is rarely used; it is used when the unenhanced imag- ing is not available and an incidental nodule is de- tected in real time in an at-risk patient who is still near the CT scanner and can complete delayed imaging. It is calculated as: (1-minute HU - 15-minute HU)/1-minute HU x 100.
An APW greater than or equal to 60% has sensi- tivity of 88% to 98% and a specificity of 92% to 96% for the diagnosis of adrenal adenoma; an RPW greater than or equal to 40% has a sensitivity of 96% and a specificity of 100% for the diagnosis of adrenal adenoma (see Box 3).36-38 The calcu- lated area under the curve for washout in general is 97% for the differentiation of adrenal adenomas from metastases. 36
Dual-energy CT has shown some promise for differentiating lipid-rich from lipid-poor lesions.39 Virtual unenhanced and true unenhanced datasets are similar, but not exact, which could lead to the misclassification of some lesions.40 CT histogram analysis has been explored as well,41 but the diag- nostic accuracy is not ideal and it does not see routine clinical use.
MR Imaging
Chemical shift MR imaging takes advantage of the lipid content of adenomas, in which intravoxel lipid is seen as nonlinear signal loss within a nodule on opposed-phase imaging (see Box 3). It is impor- tant for the longer echo time of the dual-echo sequence to be the in-phase echo to ensure that the signal loss is related to lipid and not to T2* ef- fects. Adenomas characteristically show homoge- neous signal loss on opposed-phase imaging, but occasionally heterogeneous signal loss is seen instead (Fig. 10).42 Following contrast admin- istration, adenomas generally enhance homoge- neously, but the presence of cystic change or hemorrhage within some adenomas may cause heterogeneous enhancement.43 Signal intensity washout calculations are not commonly used for the characterization of adrenal nodules in the
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way APW is used with CT. In general, apparent diffusion coefficient (ADC) values are not useful in differentiating adrenal masses, but, in indetermi- nate masses, higher ADC values are more likely to be benign.44
Both qualitative and quantitative methods may be used to detect signal loss in adrenal adenomas. Visual qualitative analysis of signal loss in an adre- nal mass may be compared with splenic signal in- tensity change; this has been shown to be as effective as quantitative methods.45 Quantitative methods include the adrenal/spleen ratio and the signal intensity index (SII).41 SII is calculated as (SI in - SI out)/SI in, and an SII greater than 16.5% is classically characteristic of an
adenoma.46 However, the SII threshold varies by the field strength and pulse sequence selection (eg, two dimensional vs 3D).
Overall, MR imaging with chemical shift imaging has a sensitivity of 87% to 100% and a specificity of 92% to 100% for the diagnosis of adrenal ade- noma. 47-49 When comparing CT washout with chemical shift MR imaging for adenoma diagnosis, the CT APW was superior, with a reported sensi- tivity, specificity, and accuracy of 84%, 79%, and 83%, compared with 67%, 89%, and 74%, respectively, for SII calculations.5º A potential pitfall is seen in adenomas with low lipid/water ra- tio, or lipid-poor adenomas, in which there may be no appreciable signal loss on opposed-phase
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imaging. Studies have evaluated the utility of chemical shift imaging for adenomas that measure greater than 10 HU on unenhanced CT, and have shown that chemical shift imaging may be inferior to APW for adrenal masses that are greater than 20 to 30 HU on unenhanced CT.51,52
An important pitfall of chemical shift imaging is that nonadenomas can also show signal loss on opposed-phase imaging. These nonadenomas include adrenocortical carcinoma (rare, generally large and heterogeneous), pheochromocytoma (rare), and certain metastases from primary lipid- containing tumors such as clear cell renal cell car- cinoma and hepatocellular carcinoma (see Box 4).53,54 Patients with such metastases gener- ally have a personal history of that tumor type.
Another potential pitfall is the rare collision tumor, in which a metastasis arises adjacent to a benign adrenal mass (Fig. 11). When present, 2 distinct regions of varying signal intensity are generally seen.
PET/Computed Tomography/MR Imaging
FDG-PET/CT has been shown to be highly sensi- tive and specific for the identification of benign and malignant adrenal masses (Fig. 12). Quantita- tive (SUV) and qualitative (signal intensity relative to background liver) methods have been used. For the identification of benign masses, FDG- PET/CT has a reported sensitivity, specificity, pos- itive predictive value, negative predictive value,
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Box 5
What the referring physician needs to know
Benign leave-alone masses, such as myelolipomas, cysts, pseudocysts, and nonhyperfunctioning ade- nomas, do not require further characterization or imaging.
Potentially malignant masses, including new or enlarging masses, masses greater than 4 cm, heteroge- neous masses, and those with irregular margins or necrosis, require further evaluation with biochemical studies, biopsy, and/or resection. Suspected adrenocortical cancer should not be biopsied before resection.
CT or MR imaging may be used to differentiate adenomas from metastases. CT and MR imaging cannot differentiate functioning from nonfunctioning adenomas, or adenomas from some pheochromocytomas.
and accuracy of 99%, 100%, 100%, 93%, and 99%, respectively.6 FDG-PET/CT also excels at the detection of distant metastatic disease in pa- tients with adrenocortical carcinoma or adrenal metastasis. False-positive findings on FDG-PET/ CT can be seen in some adrenal adenomas, adre- nal hyperplasia, and in inflammatory conditions that affect the adrenal glands. False-negative FDG-PET/CT is occasionally seen in the setting of coexistent adrenal hemorrhage or extensive necrosis.
Percutaneous Biopsy
Percutaneous biopsy of the adrenal gland has become much less common since the advent of noninvasive methods of adrenal nodule character- ization. However, in the setting of an indeterminate adrenal mass in a patient with a known primary malignancy, percutaneous biopsy may be required. Although ultrasonography-guided adre- nal mass biopsy is feasible, CT-guided adrenal mass biopsy is more common. CT-guided adrenal mass biopsy has been shown to be both safe and accurate, with an overall accuracy of 90% and a major complication rate of only 2.8% in a 10-year series of 270 patients. 55
CT-guided adrenal mass biopsy is often per- formed with the patient in the ipsilateral decubitus position to compress the ipsilateral lung, mini- mizing the risk of pneumothorax and decreasing ipsilateral motion. Angling the CT gantry is also commonly used to allow visualization of the entire needle along an angled caudal-to-cephalad approach. This approach also minimizes the risk of pneumothorax. For right adrenal nodules, this is often challenging because of the location of the right kidney, so a transhepatic approach may be used instead.
Pneumothorax and tumor seeding are uncom- mon risks of most adrenal biopsies, with 1 caveat: a suspected adrenocortical carcinoma should not be biopsied in a surgical candidate because it can render the patient incurable from tumor spillage
(the patient instead should move directly to resec- tion). Before biopsy of an indeterminate adrenal mass, the diagnosis of a pheochromocytoma should be excluded by biochemical analysis to avoid an adrenergic crisis.56
SUMMARY
The adrenal glands are a common site for benign and malignant tumors. Incidental adrenal masses are commonly encountered and almost always benign. Management guidelines are based on mass size, mass morphologic characteristics, and patient history. In patients with biochemical evidence of hormonal excess, imaging and image-guided intervention (ie, adrenal vein sam- pling) plays critical roles in localizing the site of hormone production and in guiding therapy. In pa- tients with a known primary malignancy, CT, MR imaging, and FDG-PET/CT allow the noninvasive differentiation of adenoma from metastasis in most cases. In some situations, percutaneous bi- opsy or surgical resection may be required for indeterminate or aggressive adrenal masses (Box 5).
REFERENCES
1. Greenfield LJ, Mulholland MW. Surgery: scientific principles and practice. 3rd edition. Philadelphia: Lippincott Williams & Wilkins; 2001.
2. Lockhart ME, Smith JK, Kenney PJ. Imaging of adre- nal masses. Eur J Radiol 2002;41(2):95-112.
3. Krebs TL, Wagner BJ. The adrenal gland: radiologic-pathologic correlation. Magn Reson Im- aging Clin N Am 1997;5(1):127-46.
4. Bagheri B, Maurer AH, Cone L, et al. Characteriza- tion of the normal adrenal gland with 18F-FDG PET/CT. J Nucl Med 2004;45(8): 1340-3.
5. Greenblatt DY, Shenker Y, Chen H. The utility of metaiodobenzylguanidine (MIBG) scintigraphy in patients with pheochromocytoma. Ann Surg Oncol 2008; 15(3):900-5.
6. Boland GW, Blake MA, Holalkere NS, et al. PET/CT for the characterization of adrenal masses in pa- tients with cancer: qualitative versus quantitative ac- curacy in 150 consecutive patients. AJR Am J Roentgenol 2009;192(4):956-62.
7. Berland LL, Silverman SG, Gore RM, et al. Managing incidental findings on abdominal CT: white paper of the ACR incidental findings committee. J Am Coll Radiol 2010;7(10):754-73.
8. Song JH, Chaudhry FS, Mayo-Smith WW. The inci- dental indeterminate adrenal mass on CT (>10 H) in patients without cancer: is further imaging neces- sary? Follow-up of 321 consecutive indeterminate adrenal masses. AJR Am J Roentgenol 2007; 189(5):1119-23.
9. Sacerdote MG, Johnson PT, Fishman EK. CT of the adrenal gland: the many faces of adrenal hemor- rhage. Emerg Radiol 2012; 19(1):53-60.
10. Bradley WG Jr. MR appearance of hemorrhage in the brain. Radiology 1993; 189(1): 15-26.
11. Zeiger MA, Thompson GB, Duh QY, et al. The Amer- ican Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medi- cal guidelines for the management of adrenal inci- dentalomas. Endocr Pract 2009;15(Suppl 1):1-20.
12. Dunnick NR, Leight GS Jr, Roubidoux MA, et al. CT in the diagnosis of primary aldosteronism: sensitivity in 29 patients. AJR Am J Roentgenol 1993; 160(2):321-4.
13. Elsayes KM, Narra VR, Leyendecker JR, et al. MRI of adrenal and extraadrenal pheochromocytoma. AJR Am J Roentgenol 2005;184(3):860-7.
14. Lefebvre M, Foulkes WD. Pheochromocytoma and paraganglioma syndromes: genetics and manage- ment update. Curr Oncol 2014;21(1):e8-17.
15. Lenders JW, Pacak K, Walther MM, et al. Biochem- ical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287(11):1427-34.
16. Northcutt BG, Raman SP, Long C, et al. MDCT of adrenal masses: can dual-phase enhancement pat- terns be used to differentiate adenoma and pheo- chromocytoma? AJR Am J Roentgenol 2013; 201(4):834-9.
17. Blake MA, Krishnamoorthy SK, Boland GW, et al. Low-density pheochromocytoma on CT: a mimicker of adrenal adenoma. AJR Am J Roentgenol 2003; 181(6):1663-8.
18. Patel J, Davenport MS, Cohan RH, et al. Can estab- lished CT attenuation and washout criteria for adrenal adenoma accurately exclude pheochromocytoma? AJR Am J Roentgenol 2013;201(1):122-7.
19. Miyajima A, Nakashima J, Baba S, et al. Clinical experience with incidentally discovered pheochro- mocytoma. J Urol 1997; 157(5):1566-8.
20. Shulkin BL, Thompson NW, Shapiro B, et al. Pheo- chromocytomas: imaging with 2-[fluorine-18]fluoro- 2-deoxy-D-glucose PET. Radiology 1999;212(1): 35-41.
21. Wolf FJ, Dupuy DE, Machan JT, et al. Adrenal neo- plasms: effectiveness and safety of CT-guided abla- tion of 23 tumors in 22 patients. Eur J Radiol 2012; 81(8):1717-23.
22. Kumar P, Bryant T, Breen D, et al. Transarterial embolization and doxorubicin eluting beads- transarterial chemoembolization (DEB-TACE) of malignant extra-adrenal pheochromocytoma. Cardi- ovasc Intervent Radiol 2011;34(6):1325-9.
23. Gonias S, Goldsby R, Matthay KK, et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocy- toma and paraganglioma. J Clin Oncol 2009; 27(25):4162-8.
24. Bharwani N, Rockall AG, Sahdev A, et al. Adreno- cortical carcinoma: the range of appearances on CT and MRI. AJR Am J Roentgenol 2011;196(6): W706-14.
25. Fishman EK, Deutch BM, Hartman DS, et al. Primary adrenocortical carcinoma: CT evaluation with clinical correlation. AJR Am J Roentgenol 1987;148(3):531-5.
26. Hussain S, Belldegrun A, Seltzer SE, et al. Differen- tiation of malignant from benign adrenal masses: predictive indices on computed tomography. AJR Am J Roentgenol 1985;144(1):61-5.
27. Slattery JM, Blake MA, Kalra MK, et al. Adrenocor- tical carcinoma: contrast washout characteristics on CT. AJR Am J Roentgenol 2006;187(1):W21-4.
28. Ferrozzi F, Bova D. CT and MR demonstration of fat within an adrenal cortical carcinoma. Abdom Imag- ing 1995;20(3):272-4.
29. Szolar DH, Korobkin M, Reittner P, et al. Adreno- cortical carcinomas and adrenal pheochromocy- tomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT. Radiology 2005; 234(2):479-85.
30. Groussin L, Bonardel G, Silvera S, et al. 18F-Fluoro- deoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients. J Clin Endocrinol Metab 2009;94(5):1713-22.
31. Becherer A, Vierhapper H, Potzi C, et al. FDG-PET in adrenocortical carcinoma. Cancer Biother Radio- pharm 2001;16(4):289-95.
32. Fowler AM, Burda JF, Kim SK. Adrenal artery embolization: anatomy, indications, and technical considerations. AJR Am J Roentgenol 2013;201(1): 190-201.
33. Wood BJ, Abraham J, Hvizda JL, et al. Radiofre- quency ablation of adrenal tumors and adrenocor- tical carcinoma metastases. Cancer 2003;97(3): 554-60.
34. Korobkin M, Giordano TJ, Brodeur FJ, et al. Adrenal adenomas: relationship between histologic lipid and CT and MR findings. Radiology 1996;200(3):743-7.
35. Boland GW, Lee MJ, Gazelle GS, et al. Characteriza- tion of adrenal masses using unenhanced CT: an
analysis of the CT literature. AJR Am J Roentgenol 1998; 171(1):201-4.
36. Korobkin M, Brodeur FJ, Francis IR, et al. CT time- attenuation washout curves of adrenal adenomas and nonadenomas. AJR Am J Roentgenol 1998; 170(3):747-52.
37. Caoili EM, Korobkin M, Francis IR, et al. Delayed enhanced CT of lipid-poor adrenal adenomas. AJR Am J Roentgenol 2000; 175(5): 1411-5.
38. Caoili EM, Korobkin M, Francis IR, et al. Adrenal masses: characterization with combined unen- hanced and delayed enhanced CT. Radiology 2002;222(3):629-33.
39. Morgan DE, Weber AC, Lockhart ME, et al. Differen- tiation of high lipid content from low lipid content ad- renal lesions using single-source rapid kilovolt (peak)-switching dual-energy multidetector CT. J Comput Assist Tomogr 2013;37(6):937-43.
40. Ho LM, Marin D, Neville AM, et al. Characterization of adrenal nodules with dual-energy CT: can virtual unenhanced attenuation values replace true unen- hanced attenuation values? AJR Am J Roentgenol 2012; 198(4):840-5.
41. Jhaveri KS, Wong F, Ghai S, et al. Comparison of CT histogram analysis and chemical shift MRI in the characterization of indeterminate adrenal nodules. AJR Am J Roentgenol 2006; 187(5): 1303-8.
42. Gabriel H, Pizzitola V, McComb EN, et al. Adrenal le- sions with heterogeneous suppression on chemical shift imaging: clinical implications. J Magn Reson Imaging 2004; 19(3):308-16.
43. Semelka RC, Shoenut JP, Lawrence PH, et al. Eval- uation of adrenal masses with gadolinium enhance- ment and fat-suppressed MR imaging. J Magn Reson Imaging 1993;3(2):337-43.
44. Sandrasegaran K, Patel AA, Ramaswamy R, et al. Characterization of adrenal masses with diffusion- weighted imaging. AJR Am J Roentgenol 2011; 197(1):132-8.
45. Mayo-Smith WW, Lee MJ, McNicholas MM, et al. Characterization of adrenal masses (<5 cm) by use of chemical shift MR imaging: observer perfor- mance versus quantitative measures. AJR Am J Roentgenol 1995; 165(1):91-5.
46. Fujiyoshi F, Nakajo M, Fukukura Y, et al. Character- ization of adrenal tumors by chemical shift fast
low-angle shot MR imaging: comparison of four methods of quantitative evaluation. AJR Am J Roent- genol 2003; 180(6):1649-57.
47. Outwater EK, Siegelman ES, Radecki PD, et al. Distinction between benign and malignant adrenal masses: value of T1-weighted chemical-shift MR im- aging. AJR Am J Roentgenol 1995; 165(3):579-83.
48. Israel GM, Korobkin M, Wang C, et al. Comparison of unenhanced CT and chemical shift MRI in evalu- ating lipid-rich adrenal adenomas. AJR Am J Roent- genol 2004;183(1):215-9.
49. Haider MA, Ghai S, Jhaveri K, et al. Chemical shift MR imaging of hyperattenuating (>10 HU) adrenal masses: does it still have a role? Radiology 2004; 231(3):711-6.
50. Koo HJ, Choi HJ, Kim HJ, et al. The value of 15-min- ute delayed contrast-enhanced CT to differentiate hyperattenuating adrenal masses compared with chemical shift MR imaging. Eur Radiol 2014;24(6): 1410-20.
51. Outwater EK, Siegelman ES, Huang AB, et al. Adre- nal masses: correlation between CT attenuation value and chemical shift ratio at MR imaging with in-phase and opposed-phase sequences. Radi- ology 1996;200(3):749-52.
52. Seo JM, Park BK, Park SY, et al. Characterization of lipid-poor adrenal adenoma: chemical-shift MRI and washout CT. AJR Am J Roentgenol 2014;202(5): 1043-50.
53. Shinozaki K, Yoshimitsu K, Honda H, et al. Metasta- tic adrenal tumor from clear-cell renal cell carci- noma: a pitfall of chemical shift MR imaging. Abdom Imaging 2001;26(4):439-42.
54. Sydow BD, Rosen MA, Siegelman ES. Intracellular lipid within metastatic hepatocellular carcinoma of the adrenal gland: a potential diagnostic pitfall of chemical shift imaging of the adrenal gland. AJR Am J Roentgenol 2006;187(5):W550-1.
55. Welch TJ, Sheedy PF 2nd, Stephens DH, et al. Percutaneous adrenal biopsy: review of a 10-year experience. Radiology 1994; 193(2):341-4.
56. Casola G, Nicolet V, vanSonnenberg E, et al. Unsus- pected pheochromocytoma: risk of blood-pressure alterations during percutaneous adrenal biopsy. Radiology 1986; 159(3):733-5.