Review

Continuing Medical EducationNature Reviews Urology 6, 363-373 (July 2009) | doi:10.1038/nrurol.2009.100

Subject Category: Imaging and radiology

Contemporary imaging of incidentally discovered adrenal masses

Milton D. Gross1,4, Melvyn Korobkin2, Wessam Bou Assaly3, Ben Dwamena4 & Mehdi Djekidel1  About the authors

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Learning objectives

Upon completion of this activity, participants should be able to:

  1. Describe the epidemiology of adrenal masses.
  2. List characteristics on imaging of different benign adrenal masses.
  3. Describe malignant adrenal lesions.
  4. Identify the recommended first radiopharmaceutical agent to use with scintigraphy among patients with adrenal masses and no history of cancer.

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The incidental discovery of adrenal masses during modern diagnostic imaging is a common occurrence. These masses form part of a long differential diagnostic list; most often, they are benign adrenal adenomas, but their discovery requires a clinical evaluation that is sufficiently broad to exclude clinically silent endocrine disease, metastases to the adrenal gland in patients with suspected or known malignancies, and rare adrenocortical carcinomas. CT, MRI and nuclear medicine approaches have all been used to evaluate incidentally discovered adrenal masses. Each technology provides information that contributes to the noninvasive characterization of the majority of these neoplasms. Understanding of the modalities used to assess an unanticipated adrenal mass allows for more rapid diagnosis and cost avoidance in a condition that has been referred to as a 'disease' of modern imaging technology.

Key points

  • Incidentally discovered adrenal masses are commonly encountered when modern high-resolution imaging techniques are used
  • The differential diagnostic list of incidentally discovered masses is large; most are benign, adrenal adenomas
  • The first step in the evaluation of an incidentally discovered adrenal mass is a biochemical evaluation that is sufficient to exclude clinically silent endocrine disease (such as hypercortisolism, hypercatecholaminemia, aldosteronism, and so on)
  • Noninvasive imaging techniques can be used to characterize incidentally discovered adrenal masses, and to distinguish adrenal adenomas from metastases to the adrenal glands and other adrenal neoplasms
  • An understanding of the imaging techniques used to distinguish benign from malignant and other incidentally discovered adrenal masses allows for rapid diagnosis, optimal therapy and decreased costs in the evaluation of these neoplasms

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Introduction

Since the early 1980s, the availability of high-resolution CT and MRI has resulted in the increasingly more frequent 'incidental' discovery of clinically unsuspected adrenal masses. The most important clinical issue posed by detection of these masses is their etiology, and distinguishing benign lesions from those masses that would alter patient morbidity and mortality.

Adrenal masses are detected in 0.4–4.5% of patients undergoing CT imaging for reasons other than adrenal disease (Box 1).1, 2, 3 The majority of these masses are benign and nonhyperfunctional, and represent 70–94% of all adrenal masses in patients with no history of malignancy; in patients with malignancy, the incidence of unsuspected adrenal masses ranges from 7% to 68%.1, 2, 3 Adrenal metastases have been reported in up to 21% of patients who have no documented primary tumors and in 32–73% of patients with a confirmed malignancy elsewhere.1, 2, 3

There is no sex predilection, but the incidence of clinically inapparent adrenal masses does increase with age (above the age of 30 years).1 Clinically silent hypersecretory adrenal masses of all types have been reported, including those that secrete glucocorticoids, mineralocorticoids, sex hormones and catecholamines; it is critically important to perform a biochemical evaluation to exclude—at a minimum—pheochromocytoma, normokalemic primary aldosteronism and subclinical hypercortisolism.1, 4 Obviously, a clinically silent or otherwise hyperfunctioning adrenal mass would best be treated by surgery, either using a laparoscopic or more-extensive approach, depending on the nature of the lesion.3, 4, 5, 6

A significant body of literature on incidentally discovered adrenal masses has developed since publication of the landmark National Institute of Health consensus and state-of-the-science statement on "management of the clinically inapparent adrenal mass (incidentaloma)" in 2002, and offers a variety of approaches to their evaluation and management.7 This literature includes diagnostic algorithms using CT, MRI, combined PET/CT, single photon emission tomography (SPECT)/CT and unique modifications of these imaging techniques that are designed to improve sensitivity and specificity in the evaluation of incidentally discovered adrenal masses.2, 5 In this Review we seek to update the approach to the incidentally discovered adrenal mass, a clinical dilemma arising from the proliferation of modern, high-resolution medical imaging.

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Imaging the adrenal gland

The presence of unsuspected adrenal masses is most often revealed by CT, as it is the primary modality used to evaluate the chest for most known or suspected disease that is unrelated to the adrenal glands;8, 9 the imaging protocols used for such assessment usually include the abdomen (and hence, the adrenal glands). CT can provide an image of the adrenal anatomy and guide therapy in patients with incidentally discovered adrenal masses.8, 9 MRI also distinguishes normal from abnormal adrenal glands, with a diagnostic accuracy similar to that of CT. MRI is frequently used to characterize incidentally discovered adrenal masses, especially in instances for which CT is nondiagnostic, such as in the patient with metallic clip artifacts or complex masses with variable density.8, 9

CT

The adrenal glands can be visualized in almost all patients with suspected adrenal pathology using contemporary CT scanners with an axial slice thickness of 3–5 mm. Sequential noncontrast and contrast-enhanced CT studies are useful for differentiating 'true' adrenal masses from so-called 'pseudo' tumors, which are created by adjacent structures (for example, the stomach or spleen), and for evaluating contrast-enhancement patterns (retention and washout of contrast medium) of masses. These patterns are an important characteristic used to differentiate adenomas from metastases to the adrenals and other adrenal neoplasms. Adaptations to the contrast washout approach include histogram analysis of attenuation, which provides a means of more-accurately assessing the lipid content of adrenal masses.8 Coregistered PET and SPECT/CT studies using a variety of radiopharmaceuticals (that is, radiolabeled carrier molecules) targeted at various characteristics of adrenocortical and adrenomedullary function provide additional ways of evaluating adrenal masses. These studies simultaneously combine anatomic cross-sectional information with functional, scintigraphic maps, which can improve the differentiation of benign from malignant lesions.10

MRI

Advances in MRI technology with enhanced spatial resolution have improved characterization of normal adrenal glands and small adrenal masses. The image quality of gradient-echo breath-hold scans, chemical-shift MRI with in-phase and opposed-phase imaging, and dynamic contrast-enhanced MRI to detect lipid content in adrenal adenomas with reproducible methods to calculate shift ratios allows excellent depiction of the adrenal glands by MRI with an efficacy similar to that of CT.8, 9, 11, 12

Scintigraphy

The first successful adrenal cortical imaging studies were performed in 1971 using the radioiodinated compound iodine-131-19-iodocholesterol ([131I]-19-iodocholesterol) to depict the adrenal glands in a patient with Cushing disease.13 Shortly thereafter, the radiolabeled analogs [131I]-6beta-iodomethyl-19-norcholesterol (NP-59) and selenium-75-6beta-iodomethyl-19-norcholesterol (Scintadren) were shown to produce better quality scans than [131I]-19-iodocholesterol and have been used to image the adrenal cortex since the late 1970s.14, 15

Radiolabeled inhibitors of the intermediate enzymes involved in adrenal steroid hormone biosynthesis have also been used to image the adrenal cortex.16 Metyrapone and its analogs have shown only limited success, but another 11beta-hydroxylase inhibitor, carbon-11-metomidate ([11C]-MTO), has been successfully used to depict adrenocortical neoplasms; in preliminary studies, fluorine-18-MTO [18F]-MTO has been used to image normal human adrenal glands with PET/CT.17, 18, 19 Other substrates that can be used to assess metabolic processes, such as [18F]-fluorodeoxyglucose ([18F]-FDG), a radiolabeled glucose analog that targets glucose transporter activity, have been used to identify primary adrenal neoplasms and metastases to the adrenals, whereas [11C]-labeled acetate and choline labeled with either carbon-11 or fluorine-18 have been reported to image adrenal adenomas.20

As key secretory products of the adrenal medulla, catecholamines, and their analogs, were the first of many agents studied as possible radiopharmaceuticals for adrenomedullary imaging. It was not, however, until radiolabeled metaiodobenzylguanidine (MIBG) was used that the medulla and neoplasms of adrenomedullary origin could be localized using nuclear medicine techniques.21 The accumulation of MIBG in the medulla occurs via norepinephrine-reuptake mechanisms into the catecholamine storage vesicles of adrenergic tissues.22 Alternatively, hydroxyephedrine, an analog of norepinephrine that can be labeled with [11C] or [18F], is concentrated in adrenergic nerve terminals by catecholamine uptake and storage mechanisms. Hydroxyephedrine was the first in a series of PET radiopharmaceuticals, which now includes [11C]-epinephrine, [11C] or [18F]-hydroxyepinephrine, [18F]-fluorodopamine ([18F]-FDA) and [18F]-fluorodihydroxyphenylalanine ([18F]-DOPA), that target catecholamine synthesis/reuptake pathways and can, therefore, be used to localize neoplasms of sympathomedullary origin.23, 24, 25, 26 Somatostatin receptors are expressed by neural crest cells (which give rise to, among other cell types, adrenomedullary cells), and somatostatin receptor imaging agents have been used to localize adrenomedullary and related neoplasms.27 Pentetreotide, a long-acting somatostatin analog (and antagonist), can be radiolabeled with a variety of isotopes that include indium-111, iodine-123, technetium-99m and gallium-68 for PET imaging of pheochromocytomas.24, 25, 27, 28, 29, 30 Furthermore, similar to its use in depicting other neoplasms, [18F]-FDG has been used to localize and stage primary and metastatic sympathomedullary tumors with high sensitivity and specificity.31, 32

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Characterization of adrenal masses

Myelolipoma

A myelolipoma is a benign tumor composed of bone-marrow elements that is often detected incidentally. Myelolipomas do not produce hormones, but some can become quite large and produce mass-effect symptoms, and frequently undergo spontaneous hemorrhage.33 Most myelolipomas are characterized on CT by their fat content (with CT attenuation values of -30 to -100 Hounsfield units [HU]) and frequent calcification with variable contrast-enhancing soft tissue components (Figure 1).34 The appearance of a myelolipoma on MRI, as on CT, reflects the fat-content and bone-marrow elements of the tumor. Fat exhibits high signal intensity on both T1-weighted and T2-weighted imaging sequences and fat suppression imaging algorithms show loss of signal intensity. Bone-marrow elements demonstrate low signal intensity on T1-weighted images and moderate signal intensity on T2-weighted scans, with differing degrees of contrast enhancement.35


Adrenal cyst

Adrenal cysts occur infrequently, but show a 3 : 1 female predilection; adrenal cysts can be pathologically classified into four types, of which the endothelial type is the most common.36 Adrenal cysts are detected by CT as nonenhancing masses; MRI shows them to be hypointense on T1-weighted images and hyperintense on T2-weighted images, without soft tissue or internal enhancement.37 Adrenal pseudocysts can have a complex appearance on ultrasound, CT and MRI, containing multiple internal septations, blood products or soft tissues (Figure 2).12


Adrenal hemorrhage

Adrenal hemorrhage can be bilateral or unilateral. Bilateral hemorrhage is often associated with disorders of coagulation or blood dyscrasias, and less commonly with surgical stress, sepsis, hypotension or trauma.38 Unilateral adrenal hemorrhage occurs after abdominal trauma and usually affects the right gland more often than the left.39 Acute or subacute adrenal hemorrhage exhibits unenhanced attenuation values of 55–90 HU (Figure 3). A post-traumatic, hyperdense adrenal mass shown by contrast-enhanced CT is assumed to be a hematoma; however, an unrelated adrenal neoplasm can only be excluded by unenhanced CT or serial CT follow-up. Similarly, MRI might reveal hemorrhage by high signal intensity on T1-weighted scans as a result of the methemoglobin content (a form of hemoglobin that does not carry oxygen).40, 41


Adrenal adenoma

Adrenal adenomas often exhibit HU values in the range of normal adrenal tissues. As most adenomas contain large amounts of lipid, many are hypodense, with HU values near to that of water on unenhanced CT (Figure 4).42 Adenomas show significant enhancement after intravenous administration of contrast, and exhibit more-rapid contrast washout than adrenal metastases.43, 44 Calcification in adrenal adenomas is an unusual finding.

Figure 4 | Abdominal CT scan in a patient with nonspecific abdominal pain.
Figure 4 : Abdominal CT scan in a patient with nonspecific abdominal pain. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comAn incidentally discovered left adrenal mass is seen with precontrast density of 9.8 HU characteristic of a lipid-containing adrenal adenoma.

MRI characteristics of adenomas are similar to those of normal adrenal tissues. Although the signal intensity of adenomas tends to be low on T2-weighted sequences, there is a significant overlap (20–30%) with the signal intensity of metastases. Chemical-shift imaging can be used to assess the lipid content of a tissue and is often used to distinguish adenomas from metastases, with high sensitivity and specificity.8, 45, 46

Pheochromocytoma

Approximately 10% of pheochromocytomas are clinically silent and present on anatomic imaging as incidentally discovered adrenal masses.47, 48 When a pheochromocytoma is suspected, based upon elevated catecholamines or metabolites, CT is usually the first study of choice for tumor localization. If no mass is detected in the adrenal glands, the abdominal para-aortic region is the next location to investigate, as approximately 10% of pheochromocytomas are extra-adrenal.

Pheochromocytomas show enhancement with intravenous contrast agents in patterns not unlike those of malignant adrenal masses, but occasionally these neoplasms can exhibit contrast washout characteristics similar to those of benign adenomas. These conflicting outcomes can contribute to diagnostic confusion, and confirm the importance of adequate biochemical evaluation prior to imaging, especially in instances in which there is a high clinical suspicion of pheochromocytoma.49 Previous concerns regarding the potential of intravenous contrast agents to induce hypertensive crisis have recently been alleviated with the use of nonionic contrast agents.50 Not unlike the imaging variability seen with CT, the appearance of a pheochromocytoma by MRI is usually T2 hyperintense; however, approximately 30% of these tumors might be hypointense on T2-weighted images (Figure 5).51

Figure 5 | Abdominal MRI scans of a patient with hypertension and hypercatecholaminemia.
Figure 5 : Abdominal MRI scans of a patient with hypertension and hypercatecholaminemia. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma | T2-hyperintense right adrenal gland nodule. b | In-phase MRI sequence. c | Out-of-phase MRI sequence shows no drop in signal (compare with b). d | Pre-gadolinium-enhanced image. e | Post-gadolinium-enhanced image shows mild homogenous enhancement (compare with d).

Adrenal carcinoma

Adrenal carcinomas are rare, with an incidence of two cases per million individuals.1 Patients often present late in the course of disease with abdominal pain, a palpable abdominal mass, or symptoms and signs of hypercortisolism. Other endocrine manifestations of adrenal carcinoma infrequently include aldosteronism, virilization, and feminization. An adrenal carcinoma is depicted on CT scans as a large mass with central necrosis and calcification, and heterogeneous contrast enhancement (Figure 6).52, 53 Venous extension of adrenal tumors is common and can often be seen on contrast-enhanced images.54 Carcinomas usually appear hyperintense on both T1-weighted and T2-weighted image sequences as a result of tumor hemorrhage and central necrosis.

Figure 6 | A right adrenocortical carcinoma (arrow) with central tumor necrosis and periaortic metastases on abdominal [18F]-FDG PET/CT.
Figure 6 : A right adrenocortical carcinoma (arrow) with central tumor necrosis and periaortic metastases on abdominal [18F]-FDG PET/CT. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma | Transverse abdominal CT scan. b | Whole body, coronal [18F]-FDG scan. c | Transverse abdominal [18F]-FDG scan. Permission obtained from Elsevier Ltd © Gross, M. D. et al. Eur. J. Surg. Oncol. doi:10.1016/j.ejso.2009.01.010.

Granulomatous disease

Tuberculosis, histoplasmosis and other granulomatous diseases are usually bilateral, but can, occasionally, be sufficiently asymmetric to give an impression of a solitary adrenal mass. Generally, the findings from CT scans are nonspecific, but can reveal soft-tissue masses and cystic changes with or without calcification.55

Hemangioma

An adrenal hemangioma is a benign and somewhat unusual tumor; hemangiosarcomas of the adrenal gland are much less common.56 Neither of these neoplasms are hormonally active and most are large when discovered incidentally. On CT, hemangiomas are well-defined masses with soft-tissue density on unenhanced images and inhomogeneous enhancement after contrast. The majority of hemangiomas are calcified, either from intra-tumoral phleboliths or prior hemorrhage.57 MRI findings in hemangioma include hypointensity relative to the liver on T1-weighted imaging sequences.58 Central hyperintensity due to hemorrhage may be seen in some cases, while on T2-weighted imaging sequences these masses are hyperintense. Persistent peripheral enhancement on delayed imaging is characteristic and it is not uncommon for these tumors to be removed due to hemorrhage risk and diagnostic uncertainty in excluding malignancy.

Ganglioneuroma

Ganglioneuromas are benign tumors composed of Schwann and ganglion cells of the nervous system. Approximately 20–30% of these tumors arise in the adrenal medulla and most are detected incidentally.59, 60 Ganglioneuromas appear on CT scans as solid adrenal masses as large as 11 cm in diameter.60 Contrast-enhanced images show homogeneous to mildly heterogeneous enhancement. The signal intensity on MRI scans is less than that of liver on T1-weighted sequences, with greater heterogeneity on T2-weighted images than on enhanced CT images.12

Neuroblastoma

Neuroblastoma is a common malignancy of childhood, but it is infrequent in adults and can be located anywhere along the parasympathetic ganglia. A lack of specificity of imaging features and the more disseminated nature of this malignancy in adults compared with children generate diagnostic uncertainty in differential diagnosis; lymphoma or metastatic disease are often explored as more likely possibilities. Calcification of this type of tumor, a hallmark finding in children, is uncommon in adults.12

Lymphoma

Primary lymphoma of the adrenal glands is rare; secondary involvement, with extension of retroperitoneal lymphoma into the adrenals is common in non-Hodgkin lymphoma.61, 62 Adrenal lymphoma might appear as discrete masses or a diffuse spread without major changes in adrenal gland contour by CT. Extensive involvement of retroperitoneal tumor might result in engulfment of the adrenal glands. Enhancement by contrast agents in lymphoma is less than in large vascular structures, such as the aorta or inferior vena cava. On MRI, lymphoma has lower signal intensity than liver on T1-weighted images, and is typically heterogeneous and hyperintense on T2-weighted imaging sequences.61, 62

Adrenal metastases

The adrenal glands are common sites of remote metastatic disease with an incidence of 27% in autopsy series of malignant epithelial neoplasms.63 The most common neoplasms that metastasize to the adrenal glands are carcinomas of the lung and breast, and melanoma.1 Adrenal gland metastases can be unilateral or bilateral, and can be variable in size. CT and MRI features are nonspecific. Small metastases are often homogeneous on contrast-enhanced CT or MRI, whereas large metastases often have a heterogeneous appearance owing to foci of necrosis or hemorrhage (Figure 7).12

Figure 7 | Adrenal metastases.
Figure 7 : Adrenal metastases. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma | A right upper lobe speculated mass. b | Mediastinal lymphadenopathy associated with the mass. c | and d | Abdominal CT scans depict bilateral, adrenal masses with heterogeneous density and central necrosis of adrenal metastases from a non-small-cell lung cancer.

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Adrenal masses: benign or malignant?

Unenhanced CT densitometry can be used to distinguish adrenal adenomas from metastases, as most adenomas have unenhanced CT attenuation values that are lower than those for metastases.64, 65, 66 In a patient with a known malignancy, no other evidence of distant metastatic disease and an adrenal mass, the goal of noninvasive imaging is to confirm, with high sensitivity, the presence of an adenoma. The highest sensitivity (71%) and specificity (98%) figures for the diagnosis of adrenal adenomas are obtained by selecting a threshold attenuation value of 10 HU on unenhanced CT; HU values for adenomas and adrenal hyperplasia are generally lower than those of metastases to the adrenal and pheochromocytomas.66, 67

Chemical-shift MRI can also be used to differentiate adrenal adenomas from metastases. Taking advantage of the different resonant frequency peaks for the hydrogen atom in water and triglyceride (lipid) molecules, chemical-shift MRI results in a decrease in the signal intensity of tissues that contain both lipid and water (Figure 8).68 Using a breath-hold gradient-echo technique, signal intensity loss on opposed-phase versus in-phase images identifies a mixture of tissues that contain both lipids and non-lipids; these are often present in adrenal adenomas and usually absent in metastases. Analysis of in-phase and opposed-phase imaging sequences demonstrates a sensitivity of 78% and a specificity of 87% for detection of lipid in adrenal adenomas.69

Figure 8 | Abdominal MRI and CT scans of adrenal masses.
Figure 8 : Abdominal MRI and CT scans of adrenal masses. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma | Out-of-phase MRI sequence of a 3 cm left adrenal mass. Note signal drop (compared to b), which is compatible with a lipid-containing adrenal adenoma. b | In-phase MRI sequence of the mass shown in a. c | A CT scan performed to evaluate a patient with hematuria revealed an incidentally discovered 2 cm right adrenal mass. d | Multi-phase CT scan demonstrating a precontrast attenuation of 20 HU of the mass shown in c. e | Early-phase contrast CT showing enhancement to 77 HU. f | At 15 min postcontrast, attenuation of 36 HU. Contrast washout of the nodule is (77 HU - 36 HU) ÷ (77 HU - 20 HU) times 100 = 71%, which is characteristic of a lipid-poor adenoma.

In one study of 47 adrenal masses assessed using unenhanced CT densitometry and chemical-shift MRI, there was a significant inverse correlation between the findings obtained by CT attenuation and those from chemical-shift MRI, whereas six out of eight false-negative masses for adenoma were incorrect by both methods of examination.70 In a histologic and radiologic study of adrenal adenomas imaged using both CT and chemical-shift MRI there was a significant inverse correlation between the number of lipid-containing cells and the unenhanced CT attenuation value, and a positive correlation with the relative change in signal intensity on opposed-phase MRI.71 These studies confirm that unenhanced CT and chemical-shift MRI might not complement each other in the evaluation of adrenal adenomas.

Standard contrast-enhanced CT images of the adrenal glands are obtained about 60 s after initiating a bolus intravenous injection of contrast medium. Studies suggest that attenuation values of adenomas and metastases are nearly identical at this time point. However, adenomas exhibit a rapid loss of enhancement after contrast injection, and attenuation values observed 10–15 min after contrast injection (and later) can be used to differentiate adenomas from other adrenal masses.71 Although the threshold attenuation values for the diagnosis of adenoma vary, masses with attenuation values <30–40 HU on 15-min delayed contrast-enhanced CT are almost always adenomas.

In addition to delayed CT attenuation values, it is possible to determine washout as a percentage of initial enhancement; this value is independent of the type, amount, and injection rates of contrast administration.72 The optimal threshold enhancement washout at 15 min is 60%, which corresponds to a sensitivity of 88% and a specificity of 96% for diagnosis of adenoma (Figure 8).44 Lipid-poor adenomas with attenuation values >10 HU on unenhanced CT have enhancement washout values that are nearly identical to those of lipid-rich adenomas.73 Despite the strength of washout calculations, a diagnosis of adrenal adenoma cannot be confirmed in masses that contain substantial regions of necrosis or hemorrhage.12

Adenoma or carcinoma?

Although adrenal masses larger than 5–6 cm in diameter are more likely to be benign than malignant, these lesions are considered suspicious for adrenocortical carcinoma.74 Large nonhyperfunctioning pheochromocytoma or a large adrenal metastasis can appear, by CT and MRI, identical to adrenal carcinoma. The recommended size criterion for resection of adrenal masses varies widely from 3.5 to 6 cm; some clinicians advocate resection of smaller masses, but few argue against resection of masses >6 cm, regardless of their imaging characteristics. However, there is no reason to suspect that the high sensitivity and specificity of CT and MRI criteria for the diagnosis of adenoma, if applied correctly, would not be accurate for any size of adrenal mass.

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Scintigraphy of adrenal masses

Despite the important anatomic and structural detail provided by CT and MRI, scintigraphy using a variety of radiopharmaceuticals that exploit the unique characteristics of adrenal function and metabolism offers high sensitivity and specificity for characterization of incidentally discovered adrenal masses.

Iodocholesterol scintigraphy has been used to depict adrenal adenomas and to distinguish adrenocortical carcinomas, metastases, cysts, hematomas, lipomas, myelolipomas and pseudoadrenal masses.75 The presence or absence of radiocholesterol uptake in an adrenal mass can be used to distinguish a benign from a space-occupying and potentially malignant adrenal lesion, whereas a normal pattern of imaging is seen in 'pseudo' adrenal masses.75 Planar scintigraphy has a limited spatial resolution of approximately 2 cm, such that lesions <1–2 cm in diameter might be too small to accurately characterize; however, in a review of small adrenal masses, scintigraphy demonstrated high specificity for masses greater than or equal to1 cm in diameter.76 Increased resolution and simultaneous anatomic localization of SPECT/CT might help in the evaluation of smaller adrenal masses.

NP-59, MIBG and FDG each target unique characteristics of adrenal gland function and can be used to assess the etiology of incidentally discovered adrenal masses. Maurea et al.77 demonstrated in adenomas that iodocholesterol imaging had positive and negative predictive values of 89% and 100%, respectively. Positive and negative predictive values for masses of adrenomedullary origin using MIBG were 83% and 100%, respectively, and [18F]-FDG separated benign from malignant adrenal lesions with 100% sensitivity and specificity.77 These authors recommend that if functional imaging is used to evaluate an adrenal mass in patients with no history of cancer, iodocholesterol scintigraphy should be the logical first step because benign adenomas are the most common incidentally discovered adrenal masses; this approach should be followed by MIBG to identify nonhypersecreting pheochromocytoma, and [18F]-FDG if MIBG is nonlocalizing. Alternatively, in patients with malignancy or prior cancer history, [18F]-FDG should be the initial scintigraphic study followed by iodocholesterol and then MIBG.77

In a comparison of MRI and radionuclide techniques (iodocholesterol, MIBG and [18F]-FDG) in the evaluation of nonhypersecreting adrenal lesions in 30 patients (22 benign and 8 malignant) MRI showed T2 signal hyperintensity in 46% of adenomas and 100% of pheochromocytomas; chemical-shift imaging correctly identified all adenomas; and gadolinium enhancement was seen in 100% of pheochromocytomas and 63% of malignant adrenal tumors (Figure 9).78 The comparison radionuclide studies confirmed previous studies that showed increased iodocholesterol uptake in adenomas, MIBG accumulation in pheochromocytomas, and [18F]-FDG uptake in primary tumors and metastases to the adrenal glands.78

Figure 9 | Abdominal CT and PET scans of adrenal masses.
Figure 9 : Abdominal CT and PET scans of adrenal masses. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma | CT scan of an incidentally discovered right adrenal mass that later proved to be a pheochromocytoma. b | [18F]-FDG PET scan of the mass shown in a. c | CT scan of a benign incidentally discovered adrenal mass. d | [18F]-FDG PET scan of the mass depicted in c shows that accumulation of [18F]-FDG in the anatomically abnormal adrenal is less than that in the liver and compatible with a benign, nonfunctional adrenal adenoma. e | CT scan of a patient with lung cancer and small bilateral adrenal masses. f | An [18F]-FDG-PET scan of the adrenal masses depicted in e shows that the right adrenal mass is [18F]-FDG-avid, which is compatible with a metastasis, whereas the left adrenal mass has accumulated [18F]-FDG to a level similar to that of liver, which is characteristic of an adrenal adenoma. g | Combined PET/CT scan of the masses shown in e and f. h | CT scan of a right adrenal pheochromocytoma. i | [18F]-DOPA-PET scan of the pheochromocytoma shown in h. Permission obtained from Elsevier Ltd © Gross, M. D. et al. Eur. J. Surg. Oncol. doi:10.1016/j.ejso.2009.01.010.

[18F]-FDG-PET can be used to differentiate benign from malignant adrenal lesions and metastases to the adrenals (Figure 9). Metser et al.32 used [18F]-FDG-PET/CT to study adrenal masses in 150 patients. With a standardized uptake value (SUV) threshold of 3.1, [18F]-FDG-PET had a sensitivity of 98.5% and a specificity of 92%, whereas the addition of CT to FDG-PET increased specificity to 98%; with a threshold SUV of 3.1, all lesions were correctly characterized as benign or malignant. Yun et al.31 reported that, in 50 patients with known or suspected malignancy, [18F]-FDG-PET had a sensitivity of 100%, a specificity of 94% and an accuracy of 96%; altering interpretative criteria to include lesions with [18F]-FDG uptake values equal to or greater than those for the liver acting as a 'normal' comparison tissue improved the specificity of [18F]-FDG for detecting malignant adrenal lesions without decreasing the sensitivity (Figure 9). Vikram et al.79 reported 112 adrenal masses (>1 cm in diameter) in 96 patients with known malignancy. In this retrospective series, 25 of 30 patients with malignant adrenal masses and 12 of 82 with benign adrenal masses were [18F]-FDG-avid.79 The authors speculate that false-negative adrenal metastases (in which the uptake by the adrenal mass was lower than that by the liver) might have been the result of suppressive effects of prior chemotherapy on tumor glucose metabolism and [18F]-FDG uptake; furthermore, their study confirmed reports from other groups that [18F]-FDG accumulates in some benign adrenal masses.80, 81

The 11beta-hydroxylase inhibitor [11C]-MTO was compared to [18F]-FDG in 21 patients with incidentally discovered masses that included adrenocortical carcinoma, pheochromocytoma, cyst, myelolipoma, lymphoma and adrenal metastases.17 [11C]-MTO identified all lesions of adrenocortical origin, with the highest SUV (of 28) in adrenocortical carcinoma, followed by hypersecretory adrenal cortical adenomas (12.7) and nonhypersecretory adenomas (12.2); an SUV of 5.7 was reported for metastases to the adrenal glands. However, [11C]-MTO-PET cannot distinguish benign neoplasms from adrenocortical carcinoma.82, 83, 84 [18F]-FDG accumulated in pheochromocytomas and adrenocortical carcinoma, but minimal or no appreciable [18F]-FDG accumulation occurred in all nonhypersecreting and most hypersecreting adenomas (Figure 6).84

In the evaluation of suspected pheochromocytoma, imaging with [123I]-MIBG (or [131I]-MIBG, if [123I]-MIBG is unavailable) is the first choice of study. If MIBG fails to localize the tumor, then PET/CT using [18F]-dopamine or [18F]-DOPA is the next step in imaging diagnosis.85, 86, 87, 88 In a comparison of the efficacy of [18F]-FDA, [123I]-MIBG and [111In]-octreotide (a somatostatin analog) by Ilias and colleagues,89 [18F]-FDA demonstrated the highest sensitivity in the localization of intra-adrenal and metastatic pheochromocytomas, followed by [123I]-MIBG and [111In]-octreotide; for intra-adrenal pheochromocytoma, the efficacy of [18F]-FDA and [123I]-MIBG were equivalent. If [18F]-dopamine-PET or [18F]-DOPA-PET is negative, the neoplasm might have undergone malignant dedifferentiation, in which case imaging with [18F]-FDG or [111In]-pentetreotide would be useful to localize metastases that are not identified by CT and to guide subsequent therapy (Figure 9).86, 88, 90

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Conclusions

High-resolution CT, MRI and scintigraphy can all be used to distinguish adenomas from metastases to the adrenal glands and to identify, by their unique characteristics, a large number of other incidentally discovered adrenal masses. Usually the initial identifying imaging modality provides sufficient information for accurate characterization (that is, adenoma versus metastasis), but in the case of masses that are deemed 'indeterminate' (usually complex neoplasms or so-called 'lipid-poor' masses) a second modality is necessary to better define the etiology of the lesion. In instances of conflicting diagnostic information or data that support a significant or unexpected upstaging of disease that necessitates a major change in therapy (for example, an adrenocortical carcinoma or an adrenal metastasis in an oncologic patient), direct tissue examination might be the optimal approach and an adrenal biopsy would be appropriate.

Once characterized, it is rare that a mass initially depicted as 'benign' would become 'malignant'.91 However, it is possible that a biochemically inactive (that is, nonhypersecretory) mass could become hyperfunctioning, and there are reports of conversion of nonhypersecretory to hypersecretory masses, which supports the importance of regular biochemical, and perhaps anatomic, follow-up of adrenal adenomas.92, 93 The optimal biochemical evaluation for incidentally discovered adrenal masses remains controversial; however, before proceeding through any diagnostic algorithm, the first step would be to exclude clinically-silent hypersecretory masses, especially a pheochromocytoma that if undetected might result in significant patient morbidity or mortality. Thus, a logical progression of diagnostic testing based first upon screening biochemistry and then on an imaging sequence tailored to best characterize an incidentally discovered adrenal mass will allow for a more-rapid and cost-contained diagnosis and, most importantly, a favorable patient outcome.

Review criteria

In addition to the authors' expertise, a search of MEDLINE and PubMed databases was performed using the search terms: "adrenal incidentaloma", "computed tomography", "magnetic resonance", "positron emission tomography", "adrenal scintigraphy", "18F-fluorodeoxyglucose", "adrenal carcinoma", "adrenal medulla" and "pheochromocytoma".

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Acknowledgments

Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

Competing interests statement

The authors declare no competing interests.

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Author affiliations

  1. Department of Radiology, Division of Nuclear Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA.
  2. Department of Radiology, Division of Abdominal Imaging, University of Michigan Medical Center, Ann Arbor, MI, USA.
  3. Department of Veterans Affairs Health System, Radiology Service, Ann Arbor, MI, USA.
  4. Department of Veterans Affairs Health System, Nuclear Medicine Service, Ann Arbor, MI, USA.

Correspondence to: M. D. Gross, Nuclear Medicine Service (115), Department of Veterans Affairs Health System, 2215 Fuller Road, Ann Arbor, MI 48105, USA
Email: mdgross@umich.edu

Published online 9 June 2009

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