Median size of an adrenal incidentaloma at presentation is approximately 3 cm [15, 20]. Malignant potential increases with size [4, 15, 21], and adrenocortical carcinoma (ACC) accounts for 2 % of tumors up to 4 cm in size, 6 % of tumors that are 4.1–6 cm, and 25 % of tumors that are greater than 6 cm [16, 22]. In contrast, benign adrenal adenomas account for less than 15 % of masses greater than 6 cm [16]. Benign to malignant ratio has been estimated to be 5–1 5:1 at a cutoff of greater than 3 cm in diameter and 3–1 3:1 at a cutoff of greater than 4 cm [15]. While masses greater than 6 cm should be considered malignant until proven benign and generally require surgical excision [2, 16], many experts recommend 4 cm as the cutoff diameter for surgical resection in otherwise healthy patients [2, 13, 20, 23]. The 4 cm criterion has a 93 % sensitivity and 42 % specificity for detecting malignancy and is felt to minimize number of unnecessary operations while avoid missing virtually all ACC [20, 23]. However, ACC is more commonly found in younger patients and the incidence of benign adrenal adenomas increases with age [13, 20]. Therefore, the decision regarding adrenalectomy for an incidentaloma should integrate the assessment of metabolic activity, tumor size, imaging characteristics, patient age, comorbidity status, surgical risk, presence of other malignancies, and tumor growth kinetics [2, 4, 13].

A minority of adrenal masses grow over time, with approximately 9 % growing more than 1 cm in a mean period of 3 years [15]. Even in the group of growing masses, the rate of malignant transformation is exceedingly low at around 1 in 1000, with rapid growth as a worrisome sign [13, 15, 24]. Growth by 1 cm or more during the period of observation has been recommended as a criterion to consider surgical removal [4, 13, 15]. The current recommendations for for repeat imaging are at 6, 12, and 24 months [2, 4, 13, 16, 25]. Suspicious and unusual masses may require more frequent imaging protocol, while small (<2 cm), uniform, hypodense nodules in patients with no history of malignant disease may be monitored less frequently [13].

Adrenal biopsy has limited role in the workup of adrenal masses. While biopsies have high positive and negative predictive values in patients with a known non-adrenal malignancy [26, 27], they cannot reliably differentiate benign from malignant adrenocortical tumors [2, 4, 13, 16, 23]. Although complication rate for adrenal biopsies is low, some complications, such as needle track seeding, hemorrhage, pneumothorax, and hemothorax, can seriously affect patient well-being and limit surgical options [2, 4, 13, 23]. Therefore, adrenal biopsy should be pursued only when its result is certain to influence management and radiologic and metabolic diagnostic limitations have been reached [2, 4, 13]. Prior to performing an adrenal biopsy, the possibility of pheochromocytoma must be evaluated with metabolic testing in order to prevent life-threatening hypertensive crises [16, 25].

Computed tomography (CT) and magnetic resonance imaging (MRI) are able to discriminate with high degree of accuracy among the various types of incidentally detected adrenal lesions [3], but ultrasonography is suboptimal for detection and characterization of adrenal tumors [28, 29]. Important attributes, such as size, laterality, homogeneity, density, and anatomic relationships, are also accurately assessed by MRI and CT [2]. Large size, irregular shape, vague contour, and invasion into surrounding structures generally indicate malignancy [29]. However, metastatic lesions can be homogeneous and similar in appearance to adenomas [30]. Characterization of adrenal lesions relies on the identification of intracellular lipid, perfusion differences, and metabolic activity that differentiate a benign adenoma from nonadenomas [30, 31]. Since most (>70 %) adrenal adenomas contain much higher intracellular lipid content than other adrenal lesions, lipid sensitive imaging is highly effective in their identification [30, 32]. Nevertheless, CT or MRI characteristics do not eliminate the need for a complete metabolic workup of all adrenal tumors [2, 16].

The ideal adrenal CT should include unenhanced, 60 s postcontrast, and 15 min postcontrast images [2, 3], but an unenhanced CT is perhaps the single best and most easily interpretable test to diagnose an adrenal adenoma [2]. Adrenal adenomas demonstrate a low attenuation value on unenhanced CT due to their high lipid content. The measurement of attenuation value should involve a region of interest (ROI) that is one-half to two-thirds of the lesion’s surface area through the center of the lesion and avoid areas of necrosis [3, 30]. A Hounsfield unit (HU) of 0 or less is 100 % specific but only 47 % sensitive for a benign adenoma [33]; an attenuation value of 10 HU or less, which is currently the most widely adopted threshold, improves the sensitivity to a clinically acceptable 71 % while maintaining specificity of 98 % [30, 34]. In order to improve the sensitivity for detection of adenomas on unenhanced CT, some have advocated use of histogram analysis, where individual attenuation values of all pixels in the ROI are plotted against their frequency, and the amount of lipid in the mass is proportional to the number of negative pixels (less than 0 HU) [3, 30]. Up to 91 % sensitivity with threshold of >10 % negative pixel has been demonstrated [35, 36], but its utility in clinical practice remains unproven [30]. Unlike an unenhanced CT, the utility of a single contrast-enhanced (CE) CT is limited as tremendous overlap in postcontrast attenuation values exists between adenomas and nonadenomas [37].

Up to 30 % of adrenal adenomas are lipid-poor and have an attenuation of greater than 10 HU on unenhanced CT, making them indistinguishable from other lesions [34]. They demonstrate rapid washout of contrast, a property that is unique to adenomas [3, 29, 30]. While the absolute attenuation measurement on a delayed CT is not useful, the ratio of adrenal attenuation comparing washout-delayed scan to the initial dynamic enhanced scan is able to characterize adrenal lesions with great precision [30]. If an unenhanced CT has been obtained, the percentage of absolute contrast enhancement washout (ACEW) can be calculated by [3, 30]:

Frequently in clinical practice, the unenhanced CT is unavailable. The relative contrast enhancement washout (RCEW) is calculated in these scenarios [3, 30]:
An ACEW of >60 % and a RCEW of >40 % after 15 min delay are both highly sensitive and specific for an adenoma (sensitivity 88 and 96 %, specificity 96 and 100 %, respectively), and these thresholds are adopted most commonly [3, 30, 38] (Fig. 26.1). Although a >50 % RCEW after 10 min has been reported to have a high sensitivity and specificity [30, 39], the 10 min protocol was later found to lack sufficient accuracy for routine clinical practice [40].

Standard adrenal MRI should include T1, T2, chemical shift imaging (CSI) in- and opposed-phase, and T1 fat-saturated sequences [3]. The normal adrenal has a uniform intermediate T1 and a low-to-intermediate T2 signal intensity, and it is better demonstrated on T1 fat-saturated images due to the suppression of signal from surrounding retroperitoneal fat [3]. CSI detects intracellular lipid in adenomas by exploiting the different frequency of proton oscillation in water and lipid molecules [3, 30, 41]. In adenomas that contain intracellular lipid, the signal intensity on opposed-phase sequences drops out compared to in-phase images, whereas it remains unchanged in malignant lesions and pheochromocytomas, which lack intracellular lipid [3, 30, 32, 41] (Fig. 26.2). In general, simple visual assessment of relative signal intensity loss is sufficient, but equivocal cases may need quantitative evaluation [3, 41, 42]. The adrenal-to-spleen chemical shift ratio of <70 or signal intensity index of >16.5 % may be used to identify lipid-rich adenoma [3, 30, 42, 43]. In lipid-rich adenoma, CSI is similar to unenhanced CT in accuracy and avoids ionizing radiation, although at significantly higher cost [30]. However, in lipid-poor adenomas, particularly those with unenhanced CT attenuation values between 10 and 30 HU, CSI appears to be superior [44, 45]. Further modification of CSI to subtraction CSI, where the opposed-phase images are subtracted from the in-phase images, can be helpful in equivocal cases to further improve diagnostic accuracy [46]. Unlike contrast-enhanced CT washout studies, gadolinium-enhanced MR washout studies do not exhibit sufficient diagnostic strength [2–4]. Nevertheless, adenomas demonstrate certain enhancement patterns that may aid in discriminating them from malignant lesions, such as homogeneous enhancement, ring enhancement, and early peak enhancement [47].

¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) has demonstrated high sensitivity and specificity in identification of malignant adrenal tumors, including adrenocortical carcinomas, metastatic pheochromocytomas, and metastatic lesions to the adrenal gland [48–50]. ¹¹C-metomidate, a radiotracer that is preferentially taken up by adrenocortical cells, is used to distinguish adrenocortical and non-cortical lesions, but its use is significantly limited by its inability to differentiate benign adenomas from adrenocortical carcinomas [51–53].

Radionuclide scintigraphy with ¹³¹I-6β-iodomethyl-norcholesterol (NP-59), another marker of adrenocortical tissue, can distinguish lesions of adrenocortical origin from other space-occupying lesions [17]. However, NP-59 is also unable to identify adrenal adenomas from adrenocortical carcinomas, and it is currently not approved by the US Food and Drug Administration [2, 3, 30]. ¹³¹I or ¹²³I metaiodobenzylguanidine (MIBG) is an analogue of norepinephrine that is incorporated into catecholamine storage vesicles and is used to identify pheochromocytomas [29, 54]. However, MIBG scintigraphy has suboptimal sensitivity and specificity, particularly in extra-adrenal, malignant, and certain familial diseases, limiting its utility [2, 50]. Overall, the indication for functional imaging in the workup of adrenal incidentalomas is restricted due to the high diagnostic accuracy of biochemical evaluation and cross-sectional imaging [2, 4, 25, 30].

More than 10 % of adrenal incidentalomas are metabolically functional [19]. Metabolic testing for cortisol and catecholamine is recommended for all adrenal incidentalomas [16]. Aldosterone hypersecretion should also be assessed in patients with a history of hypertension [13, 16, 55]. Since sex steroid hypersecretion is exceedingly rare, routine testing for sex hormones is not recommended [13, 16].