Review Article
Adrenal Radiology: Distinguishing Benign from Malignant Adrenal Masses
N. Reed Dunnick1, Melvyn Korobkin, Isaac Francis
A drenal masses are common, hav- ing been reported in as many as 9% of postmortem examinations [1]. The increasing use of cross-sectional imaging techniques (CT, sonography, and MR imaging) has resulted in more frequent detection of adrenal masses [2]. Although most incidentally discovered tumors are non- hyperfunctioning adenomas [3-6], they must be distinguished from malignant lesions, either primary or secondary. Even in patients with a known malignancy, only approxi- mately 50% [7, 8] or fewer [9] of adrenal masses are found to be metastases on biopsy. The frequency of isolated adrenal metastases is likely to vary widely with the stage and specific type of underlying malignancy. In this manuscript, we review the features of benign and malignant adrenal tumors and dis- cuss methods to distinguish between them.
Benign Masses
Miscellaneous Benign Causes
Many different benign adrenal masses may be encountered. In some cases, such as cysts, hemorrhage, and myelolipomas, the imaging features may be sufficiently charac- teristic that a confident diagnosis can be made. In many others, however, a specific benign diagnosis cannot be made and further evaluation is required.
Adenomas
Adrenal adenomas can be characterized as producing an unregulated amount of hor- mone (hyperfunctioning) or as behaving like normal adrenal cortex (nonhyperfunction- ing) [10]. Hyperfunctioning adrenal ade- nomas may be responsible for several clinical syndromes that can usually be rec- ognized clinically and confirmed biochemi- cally. The most common of these is Cushing’s syndrome, which results from excess quantities of cortisol secreted by the adrenal adenoma. Less common syndromes are Conn’s syndrome (primary aldoster- onism), which results from excess secretion of aldosterone, and the virilizing and femi- nizing syndromes. Each of these syndromes may be caused by either adrenal hyperplasia or an adrenal tumor.
Hyperfunctioning adenomas are usually small when they are detected radiographi- cally. A recent review of aldosterone-secret- ing adenomas detected by CT found the average diameter of these tumors to be less than 2 cm [11]. Adenomas secreting unregu- lated amounts of cortisol are slightly larger but are still smaller than malignant tumors causing Cushing’s syndrome [12, 13]. Ade- nomas responsible for virilization or femini- zation are rare. Detection of an adrenal mass in a patient in the appropriate clinical setting
with biochemical documentation of the dis- ease process implies a hyperfunctioning ade- noma [10]. These patients are usually cured by surgical excision of the adenoma [ 14].
Nonhyperfunctioning adrenal adenomas, 3 mm or larger, were found by Commons and Callaway [15] in 3% of 7437 postmor- tem examinations. They noted that the inci- dence of these adenomas tended to increase with age, so that they were found in 5% of patients 60 to 70 years old. This tendency for the incidence of adenomas to increase with age to a peak in the seventh or eighth decade has been confirmed by other studies [1. 16]. Furthermore, adenomas were more common in patients with hypertension and diabetes mellitus. Hedeland et al. [1] re- ported adrenal adenomas 2 mm to 4 cm in diameter in 17% of patients with diabetes mellitus and in 18% of patients with second- ary hypertension. An increased incidence of adrenal adenomas has also been reported in patients with renal carcinoma [17] and hereditary adenomatosis of the colon and rectum [18].
The typical imaging features of an adrenal adenoma are those of a small, usually homo- geneous mass. Because the masses are small, located deep within the abdomen, and sur- rounded by fat, they are often difficult to detect with sonography. On CT, these ade-
AJR 1996;167:861-867 0361-803X/96/1674-861 @ American Roentgen Ray Society
Dunnick et al.
nomas have a smooth rounded appearance (Fig. 1). The density on unenhanced scans tends to be low, often near that of water. Among hyperfunctioning adenomas, those secreting predominantly aldosterone tend to have the lowest density [11, 19]. Homoge- neous enhancement occurs after IV contrast administration.
The adrenal glands may also be imaged by MR. in which case adenomas are usually isointense with liver on both T1- and T2- weighted spin-echo sequences. Enhancement of adenomas occurs with IV administration of gadolinium diethylenetriamine pentaace- tic acid, but less than is seen with adrenal metastases.
Pheochromocytoma is considered a hyper- functioning tumor of the adrenal medulla, although an occasional nonfunctioning pheo- chromocytoma may be encountered. The characteristic features of sweating. palpita- tion, headache, and labile hypertension sug- gest the diagnosis, which may be confirmed by finding elevated serum or urine catechola- mine levels.
Sporadic pheochromocytomas are readily detected, as they average more than 4 cm in diameter [20]. Extraadrenal pheochromocyto- mas (paragangliomas) are most often in the paraaortic area and may also be identified on imaging studies [21, 22]. They appear as a soft-tissue mass on CT: larger lesions may show a central cystic component [23, 24] (Fig. 2). Intravascular contrast administration is sel- dom recommended because it may precipitate a hypertensive crisis [25]. MR is also useful for imaging pheochromocytomas as they have a high signal intensity on T2-weighted images. Radionuclide-labeled metaiodobenzylguani- dine (MIBG) is highly sensitive for detecting pheochromocytomas but is not frequently used because of the high accuracy of CT [26]. MIBG is most valuable in locating paragan- gliomas outside the abdomen.
Malignant Tumors
Malignant adrenal tumors may be either primary adrenocortical carcinomas or metastases. Occasionally, a malignant pheo- chromocytoma may be encountered. Malig- nancies that involve the adrenal glands by direct extension are usually apparent on imag- ing studies and are not included in this review.
Adrenal Carcinoma
Carcinoma of the adrenal cortex is rare. accounting for only 0.02% of all cancers [27]. The tumors are slightly more common in the left adrenal gland than in the right gland [27- 29].
The frequency with which carcinomas are nonhyperfunctioning is reported as approxi- mately 50% but varies with the series, which may reflect the diligence for which the hor- mones are searched. Some tumors likely pro- duce incomplete hormones that may still be detected by measuring levels of 17 hydroxy corticoids and 17-ketosteroids [27. 28]. The incidence of adrenal carcinoma is approxi- mately equal in men and women, although functioning tumors are more common in women [27, 29].
The active hormone most commonly pro- duced by adrenal carcinomas is cortisol, and Cushing’s syndrome is the most frequent clini- cal presentation. Occasionally patients have virilization, but feminization and Conn’s syn- drome are rare manifestations of adrenal carci- noma. Patients with nonhyperfunctioning tumors have abdominal symptoms such as pain, nausea, and vomiting or manifestations of metastatic disease.
Adrenal carcinomas are usually large at the time of clinical presentation, averaging more than 10 cm in diameter [30-32]. Occasionally tumors as small as 3 cm are seen. Generally, hyperfunctioning carcinomas are smaller than nonhyperfunctioning tumors, as the manifesta-
tions of the hormone excess bring the patient to clinical attention.
Unenhanced CT images reveal a large well- defined but inhomogeneous adrenal mass. Adjacent organs are often displaced by large tumors. Calcification is present in about 30% of cases [30]. With IV contrast administration, inhomogeneous enhancement occurs that is most pronounced in the periphery of the tumor [32] (Fig. 3).
Evidence of metastases to the liver, lung, or lymph nodes is frequently found on initial eval- uation. If surgical resection is contemplated, evaluation of extension into the inferior vena cava is critical. It is important to precisely define the extent of venous invasion, as this defines the point at which vascular control can be gained.
Adrenal carcinomas are hypointense com- pared with the liver on TI-weighted MR images and hyperintense compared with the liver on T2-weighted sequences [33]. MR imaging with gradient-echo and other vascular imaging techniques is useful in defining intra- vascular extension [10]. Coronal and sagittal MR images are more useful for revealing the most cephalad extent of intracaval tumor inva- sion than are the axial images of CT.
Metastases
The adrenal glands are a common site of metastatic disease. In their classic review of the postmortem examinations of 1000 patients with malignant neoplasms of epithe- lial origin, Abrams et al. [34] found adrenal metastases in 270 (27%). Adrenal metastases may be even more frequent now, as onco- logic patients live longer because of aggres- sive treatment, especially chemotherapy and bone marrow transplants. The most common primary malignancies in patients with adre- nal metastases are carcinomas of the breast and lung and melanoma [34, 35].
I
Fig. 2 .- Adrenal pheochromocytoma in 66-year-old woman. Enhanced CT scan shows left adrenal mass (arrow) with central region of low attenuation repre- senting hemorrhage and necrosis.
Benign Versus Malignant Adrenal Masses
The imaging features of adrenal metastases are nonspecific. Size varies from microscopic disease that cannot be detected on imaging studies to enormous masses. The small metastatic deposits are often homoge- neous, but large lesions may have irregular cystic areas because of hemorrhage or central tumor necrosis. Similarly, contrast enhance- ment is usually homogeneous in small tumors but is more likely to be heterogeneous with large lesions. The margins of small lesions are often smooth, whereas larger metastases may have irregular or lobulated contours (Fig. 4). Hemorrhage is uncommon but has been reported in patients with carcinoma of the lung and malignant melanoma [36]. Calcifica- tion is rarely seen and suggests either coexist- ing granulomatous disease or previous hemorrhage.
The MR imaging findings of adrenal metastases include an adrenal mass of varying size. Unless there is a cystic com- ponent, the tumor is often isointense or slightly less intense than the liver or spleen on TI-weighted sequences. There is, how- ever, a considerable increase in the signal intensity on T2-weighted images, possibly representing an increased water content in these adrenal lesions.
The sensitivity of CT for detecting adre- nal metastases may be low. Although adre- nal masses as small as 10 mm are often detected by CT, metastatic deposits may be even smaller. Pagani [37] biopsied 43 adre- nal glands in patients with small cell lung carcinoma and morphologically normal adrenal glands on CT. Five (17%) of the 29 biopsies with adequate cellular material were positive for metastases.
There may be many false-positive CT interpretations, as many adrenal masses in oncologic patients are not due to metastatic
disease. Oliver et al. [9] reviewed 330 patients with non-small cell bronchogenic carcinoma and found 32 patients with adre- nal masses and no other evidence of abdomi- nal metastases. Of the 25 patients who had an adrenal biopsy, only eight (32%) had metastases whereas 17 (68%) had an adrenal adenoma.
Distinguishing Benign from Malignant Causes
CT. MR imaging, and adrenal scintigra- phy may each be used to distinguish a malig- nant adrenal mass from a benign lesion. Furthermore, percutaneous adrenal biopsy may be used for tissue confirmation of a sus- pected metastasis. The method used will depend on the patient’s specific clinical set- ting as well as the facilities available and the expertise of the radiologist.
There are two common clinical settings in which it becomes important to determine whether an adrenal mass is benign or malig- nant: the patient being studied for an unrelated problem in whom an “incidental” adrenal mass is found, and the patient with an under- lying primary malignancy in whom the adre- nal mass is the only evidence of metastatic disease. In both of these clinical settings, demonstration of an adrenal malignancy may result in a profound change in evaluation and treatment.
The most likely cause of an incidental adrenal mass is a benign nonhyperfunction- ing adenoma. Other benign causes, such as a cyst, hemorrhage, or myelolipoma, have imaging features that are often sufficiently characteristic that a confident diagnosis can be made.
The possible malignant causes of an inci- dentaloma include an adrenal carcinoma and
an adrenal metastasis. Adrenal carcinomas are rare and their imaging features of a large mass, often with central necrosis, suggest the correct diagnosis, which can be confirmed by finding elevated levels of 17-ketosteroids. A metastasis would have to be the first mani- festation in a patient with an occult primary tumor, which would be rare. Thus, an adre- nal mass detected as an incidental finding is most likely benign, and an aggressive evalu- ation, especially if it includes invasive proce- dures, is not justified.
Patients who have a malignancy undergo a staging evaluation before treatment plan- ning. If widespread metastatic disease exists, the presence or absence of an adrenal metastasis has no effect on treatment or prognosis. However, if the adrenal mass is the only evidence of metastatic disease, this distinction of an adenoma from a metastasis becomes critical. Even in patients with a known primary tumor, a solitary adrenal mass is more likely benign than malignant [7-9]. However, a significant number of these masses will represent metastases. Thus a rigorous evaluation, including invasive procedures if necessary, is justified.
CT
Because CT is the technique most fre- quently used to detect adrenal masses, it is not surprising that the initial attempts to dis- tinguish adrenal adenomas from metastases were made using CT criteria. Hussain et al. [38] reviewed the CT features of 43 adrenal masses and constructed tables describing the estimated probability based on the presence or absence of these features. Hussain et al. believed that tumor size, homogeneity, and contrast enhancement were the best determi- nants. Berland et al. [39] restricted their review to masses smaller than 5 cm in diam-
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eter and reported a 100% positive predictive value for a benign diagnosis but only a 62- 82% predictive value for a malignant lesion.
Lesion size and attenuation coefficient on unenhanced scans were believed to be the best discriminators by Lee et al. [40]. For a benign adrenal mass, they reported a sensi- tivity:specificity ratio of 47:100% with a threshold of 0 H for the density of the adre- nal mass on an unenhanced CT examination and 79:96% when 10 H was used. Van Erkel et al. [41] confirmed these encouraging results and recommended a threshold of 16.5 H that produced a sensitivity:specificity ratio of 100:95% for a benign mass when applied retrospectively to their series. Similar excel- lent results were reported by Korobkin et al. [42], who found that a threshold of 18 H accurately distinguished adenomas from malignant lesions (Figs. 5 and 6).
MR Imaging
Several different MR imaging techniques have been used to distinguish benign ade- nomas from metastases. Using a 0.5-T mag- net, Reinig et al. [43] reported that metastases had a higher signal intensity than adenomas on T2-weighted images. This finding was confirmed by Glazer et al. [44] on a 0.35-T magnet and by the later work of Reinig et al. [45]. Subsequent investigation reported that benign masses may occasionally have a high T2 signal intensity [46] and that an overlap group of 20-31% exists, whether ratios of adrenal mass to liver, muscle, and fat or the absolute T2 signal intensity is measured [47]. Interestingly, both Baker et al. [47] and Kier and McCarthy [48] found that calculated T2 relaxation times were superior to the adrenal mass-liver signal intensity ratios when patients were imaged at 1.5 T [48].
In 1989, Krestin et al. [49] reported that dynamic perfusion studies after gadolinium administration could distinguish adenomas from metastases. Malignant lesions had a significantly greater enhancement and more prolonged washout of contrast agent than did adenomas. However, an overlap in enhance- ment characteristics led to an indeterminate group of nine (24%) patients. A larger series of patients found only 8% classified as inde- terminate, but there were two false-positive examinations for malignancy [50]. Subse- quent studies have not confirmed the utility of the dynamic perfusion technique [51, 52].
More recently, MR spectroscopic [53] or chemical shift imaging techniques have been used to detect lipid within an adrenal mass [51, 52, 54-58]. Because most adenomas contain lipid material and metastases do not, chemical shift imaging can readily reveal an
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Benign Versus Malignant Adrenal Masses
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adrenal mass as an adenoma when the mass loses signal and appears dark in comparison with reference tissue such as liver, muscle, or spleen [59] (Figs. 7 and 8). Thus, Mitchell et al. [54] could use chemical shift imaging to reveal lipids in 26 of 27 benign cortical masses and in none of 12 metastases. Mitch- ell et al. found that opposed-phase images were more sensitive than fat-suppressed images in revealing lipid. Using the spleen as a reference tissue eliminates potential confu- sion in patients with fatty infiltration of the liver. A modification of this technique using a fast low-angle shot sequence has shown similar excellent results [55]. However, it was recently reported that contrast agents such as gadolinium increase the signal of water within fatty tissue, which causes a par- adoxical reduction in the signal intensity on opposed-phase images [60]. More work is needed to determine the effect of contrast agents on lipid detection with chemical shift imaging.
The ability to use chemical shift imaging as a practical MR imaging technique to dis- tinguish benign from malignant adrenal lesions was further demonstrated by Outwa- ter et al. [58]. Rather than using quantitative techniques, these researchers relied on the subjective evaluation of adrenal masses on T1-weighted chemical shift MR imaging. For three interpreters, Outwater et al. found positive predictive values for a definite or probable benign lesion of 87%, 92%, and 95%. Korobkin et al. [52] and Mayo-Smith
et al. [61] have also confirmed that simple visual analysis is as effective as quantitative methods in characterizing adrenal masses as adenomas when detecting intratumoral lipid.
Adrenal Scintigraphy
Because adrenal adenomas contain func- tioning adrenal cortical cells, they will take up a cortical-labeling radionuclide tracer such as iodine-131-6ß-iodomethylnorcho- lesterol (NP-59) when bound to low-density lipoproteins. When an area of radionuclide uptake on an NP-59 scan correlates with a mass seen on a cross-sectional imaging study such as CT, the examinations are con- cordant and the mass is an adrenal adenoma [62]. If the two studies are discordant, as when an area of tracer uptake at the site of the mass is not seen, the mass is not an ade- noma but could represent a metastasis or other nonfunctioning benign lesion such as a cyst or hemorrhage. Although NP-59 is not yet approved by the United States Food and Drug Administration for general use, it is available as an investigational new drug from our institution after a physician-spon- sored investigational new drug application has been filed with the Food and Drug Administration [62-64].
Biopsy
Percutaneous biopsy may be performed to diagnose an adrenal mass of uncertain cause, but such biopsy is more commonly used to obtain tissue confirmation of a suspected
diagnosis. A posterior approach is recom- mended for left adrenal masses because nee- dles passed anteriorly often penetrate the pancreas and risk initiating pancreatitis [65]. Right adrenal masses may be reached from a transhepatic or posterior route. Either aspira- tion or core biopsy may be performed, and 18- to 21-gauge needles are most frequently used [66].
The overall accuracy of percutaneous adrenal biopsy reported by Welch et al. [66] was 90%, although they noted an improve- ment from 85% to 93% with experience. The positive predictive value of percutaneous biopsy approaches 100% for metastases because false-positive interpretations are rare. The negative predictive value, however, is approximately 80%.
If neither malignant cells nor benign adre- nal tissue is seen on the biopsy specimen, the result should be considered nondiagnostic. Patients whose biopsy results are nondiag- nostic may be successfully diagnosed with a repeat biopsy, but if not. a surgical biopsy should be considered [67].
The complication rate for percutaneous adrenal biopsy is reported to be 1-11%. Welch et al. [66] reported major complications in only eight (3%) of 277 biopsies. All eight were hematomas, one of which required an adrena- lectomy. Adrenal hematomas likely would be detected more frequently if patients were rou- tinely scanned after biopsy. Other complica- tions of percutaneous adrenal biopsy include pneumothorax and hemothorax.
Suggested Algorithm
Percutaneous biopsy is generally consid- ered the most definitive test to diagnose an adrenal metastasis. However, a significant number of nondiagnostic biopsies have been reported: 18% in the series by Silver- man et al. [67]. Furthermore, a negative predictive value of only 80% is too low to confidently exclude a metastasis. Thus, percutaneous biopsy is most useful in con- firming metastatic disease.
Chemical shift MR imaging has shown excellent results and could be justified as the primary technique to distinguish benign from malignant adrenal lesions. However, most oncologic patients undergo staging with CT and incidental adrenal masses are more likely to be found by a CT examination than by MR imaging. Thus, a CT technique remains more efficient.
The main disadvantage of CT is that most CT examinations are performed after IV con- trast administration. Thus, patients must return at a later time for an unenhanced study. However, in a preliminary report (Brodeur FJ et al., presented at the Radiological Society of North America meeting, November 1995), delayed scans performed 45-60 min after IV contrast administration have been shown to determine the benign nature of these lesions.
The precise threshold value chosen for CT may vary among scanners or institutions. In one study where McNicholas et al. [68] used a threshold of 10 H, no metastases were clas- sified as adenoma, whereas Korobkin et al. [42] were able to exclude all metastases, even at 18 H.
Conclusion
The frequent detection of incidental adre- nal masses on chest and abdominal CT exam- ination has led to extensive investigation of noninvasive techniques that can obviate per- cutaneous biopsy to exclude metastases in oncology patients and to reduce expensive imaging surveillance to exclude adrenocorti- cal carcinoma in patients without extraadrenal malignancy. Recent studies have established that both unenhanced CT densitometry and chemical shift MR imaging can accurately differentiate benign adenomas from nonade- nomatous masses, including metastases, by features that reflect the large amount of lipid found in most adenomas and absent in most nonadenomas. The large amount of intracyto- plasmic lipid results in a low unenhanced CT
attenuation value (less than 10 H) and a rela- tive signal intensity loss on chemical shift MR imaging. Although the optimal algorithm for characterizing an adrenal mass has not yet been firmly established, the use of one or both of these techniques can clearly characterize many adrenal masses as benign without the necessity of other invasive or noninvasive strategies. In institutions where NP-59 is available, radionuclide scanning is also highly accurate in characterizing many adrenal masses as cortical adenomas.
Many issues are not yet clarified. First, because many if not most adrenal masses are first detected on enhanced rather than unen- hanced CT examinations, a repeat study with- out contrast enhancement is often necessary, usually on a subsequent day. One recent study suggests that delayed enhanced CT densitom- etry 1 hr after a standard enhanced CT series may also be accurate in differentiating benign from malignant masses. Second, it is not cer- tain whether quantitative ratios of the signal intensity of adrenal masses to liver or spleen on chemical shift MR imaging need to be cal- culated, or whether qualitative assessment by visual analysis alone is sufficient. Third, the percentage of adrenal masses that require both CT densitometry and chemical shift MR imaging rather than only one of these tech- niques remains uncertain.
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