Current Status of Imaging for Adrenal Gland Tumors
Julie H. Song, MD*, William W. Mayo-Smith, MD
KEYWORDS
. Adrenal . Adrenal mass . Adrenal tumor . Adrenal incidentaloma
. Hyperfunctioning adrenal mass
KEY POINTS
· Adrenal masses are common and mostly benign in patients without known malignancy.
. Most adrenal masses can be accurately characterized by contemporary computed tomography, magnetic resonance imaging, and positron emission tomography.
· Computed tomography and magnetic resonance imaging are excellent tools in the detec- tion of clinically suspected hyperfunctioning adrenal mass.
· Appropriate utilization of imaging is important for optimal management, to separate benign inconsequential adrenal masses from those that require treatment.
The adrenal gland is a common site of disease and can harbor a wide range of pathology. Because of expanding clinical indications for cross-sectional imaging and improved spatial resolution of computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound scan, adrenal masses are now frequently discovered incidentally. The prevalence of adrenal masses at CT is approximately 5%,1-3 compa- rable to the estimated prevalence in the general population of 3% to 7%.4-6 Most ad- renal lesions are benign, most commonly nonfunctioning adenoma. However, the adrenal gland is also a common site of metastasis in oncologic patients. The adrenal gland can also be the source of hyperfunctioning tumors that require intervention and, more rarely, primary malignant neoplasms. Contemporary adrenal imaging is highly accurate in both the detection and characterization of adrenal masses. This article discusses the role of imaging in the evaluation of more common adrenal masses, with primary emphasis on CT and MRI.
PREIMAGING PLANNING Normal Adrenal Gland
The adrenal glands are well visualized on abdominal CT and MRI. They are located anterosuperiorly to the kidneys within the perirenal space, enclosed by perirenal
The authors have nothing to disclose.
Department of Diagnostic Imaging, Rhode Island Hospital, Alpert School of Medicine, Brown University, 593 Eddy Street, Providence, RI 02903, USA
* Corresponding author.
E-mail address: jsong2@lifespan.org
http://dx.doi.org/10.1016/j.soc.2014.06.002
fascia. The normal adrenal glands are homogeneous in density or signal, and have an inverted V or Y shape (Fig. 1). The arterial supply to the glands is via the superior, mid- dle, and inferior adrenal arteries (branches of the inferior phrenic artery, aorta, and renal artery, respectively). The venous drainage of the adrenal glands is predominantly by the central vein, typically draining directly into the inferior vena cava on the right and the caudal path on the left into the left renal vein. The adrenal gland is composed of the adrenal cortex and medulla, 2 functioning units with different embryologic origin and endocrine functions. The adrenal cortex secretes cortisol, aldosterone, and androgen, and the adrenal medulla secretes epinephrine and norepinephrine.
Principles and Rationales for Imaging Studies
The selection of the optimal adrenal imaging modality depends on the reason for im- aging, whether the test is for detection or characterization of an adrenal mass, as described in a later discussion. Other factors, such as contrast allergy, renal insuffi- ciency, and radiation concern may also play a role in imaging modality selection.
Detection of an abnormality is finding the lesion, most commonly to assess for metastasis in patients with an established malignancy. In this setting of metastatic workup, contrast-enhanced CT is the most appropriate tool with positron emission to- mography (PET) increasingly used in certain malignancies, such as lung cancer. Another important clinical scenario of adrenal mass detection is to localize a sus- pected hyperfunctioning tumor in a patient with biochemical evidence of hormonal excess. Either CT or MRI is used to localize most of the hyperfunctioning tumors, and occasionally metaiodobenzylguanidine scintigraphy may be necessary to localize a suspected pheochromocytoma.
Characterization of an abnormality is determining lesion histology using imaging. Certain adrenal masses have specific benign diagnostic features at detection, so that further workup is not warranted. However, adrenal masses often have a nonspe- cific appearance, especially at original contrast-enhanced CT performed for another reason. For these adrenal “incidentalomas,” defined as adrenal masses detected inci- dentally on an imaging examination performed for other reasons, the imaging goal is to separate a benign mass, most commonly an adenoma, from a mass that requires treatment. CT and MRI are the most commonly used imaging tools in characterizing adrenal masses, with PET usually reserved for patients with known extra-adrenal ma- lignancy. The imaging appearances on these studies reflect physiologic differences of
adenoma from malignant masses: intracytoplasmic lipid content, contrast washout pattern, and metabolic activity.
CT is highly accurate in diagnosing adenoma, because both lipid content and washout characteristics can be used, as discussed later. The main advantages of MRI over CT are in patients in whom iodinated contrast is contraindicated because of allergy or renal insufficiency or in young patients in whom radiation exposure is a concern. The premise behind PET imaging is that malignant tumors are usually glucose avid because of increased metabolic activity. Most metastatic adrenal masses show increased activity, whereas most benign adrenal lesions do not. The need for imaging-guided biopsy to diagnose an adrenal mass has decreased in recent years as advances in adrenal imaging now allow accurate characterization of most adrenal masses.7 The imaging modalities used to characterize adrenal masses are summarized in Table 1.
DIAGNOSTIC IMAGING TECHNIQUES
CT
Most adrenal masses are well visualized on routine abdominal CT, typically recon- structed at 5-mm thickness. Dedicated adrenal CT is performed when necessary to further characterize a known adrenal mass. Adrenal CT is performed with the patient in supine position as follows:
· Unenhanced sections are acquired through the adrenal gland with image recon- struction at 2 to 3 mm in axial and coronal planes.
. An elliptical region of interest (ROI) is placed in an adrenal mass. If the density of the adrenal mass measures ≤10 Hounsfield units (HU), then it is a benign lipid- rich adenoma and the examination is complete.
. If the density of the adrenal mass measures greater than 10 HU, then contrast material is injected intravenously.
. The next data sets are acquired at 60 seconds and 15 minutes after the start of contrast injection using the same CT acquisition parameters.
· Density measurements are obtained of the adrenal mass on unenhanced, dy- namic, and delayed imaging, and percentage of contrast washout is calculated using the formula further discussed below.
MRI
The principle MRI technique used in adrenal evaluation is chemical shift imaging (CS- MRI) obtained with in-phase and out-of-phase T1 gradient-recalled echo pulse sequences. CS-MRI exploits the different resonant frequencies of protons in fat and
| Imaging Procedure | Rationale for Selection | Issues |
|---|---|---|
| CT | Most widely available Diagnosis based on density or CT washout | Contrast allergy and renal insufficiency (when contrast is necessary for diagnosis) Radiation in young patients |
| MRI | Young patients and patients with renal insufficiency | MR incompatible device (eg, pacemaker) |
| PET | Mostly in patients with known cancer | Not recommended in patients without a known malignancy |
water molecules, with fat protons resonating at a slower frequency. Thus, at a prede- termined echo time when the protons in fat and water molecules are out of phase, the net effect is signal cancellation within a voxel compared with when the protons are in phase. Most adrenal adenomas containing sufficient amount of lipid, thus, lose signal on out of phase compared with in phase. The lipid-rich adrenal adenoma will appear dark on out-of-phase imaging. When an adrenal mass is not diagnostic of an adenoma at CS-MRI, T2-weighted sequence and gadolinium-based, contrast-enhanced series are obtained for further characterization of an adrenal mass.
PET
PET and PET-CT utilizing fluorine-18-2fluoro-2-deoxy-D-glucose (FDG) are primarily performed in oncologic patients. To achieve and optimize a diagnostic scan, patients need to refrain from significant exercise for 24 hours, and their glucose level has to be less than 200 mg/dL before PET. At total-body PET-CT, CT, and PET are acquired separately. First, the patient receives intravenous administration of the FDG radio- pharmaceutical, and then 75 minutes later, a CT without intravenous iodinated contrast is obtained followed immediately by PET acquisition. After these acquisitions, the CT images are fused (coregistered) with the metabolic PET dataset, which pro- vides accurate anatomic localization of abnormal PET activity and also allows adrenal CT density measurements. These factors improve diagnostic performance of adrenal characterization in oncology patients.
INTERPRETATION AND ASSESSMENT OF CLINICAL IMAGES Adenoma
Adenomas are the most common adrenal lesion encountered in the general popula- tion, and most are not hyperfunctioning. Adenomas are typically well-defined, round, or oval masses of smooth margins and homogeneous density. One of the key diag- nostic features of adenomas is the presence of intracellular lipid. Adrenal adenomas are composed of varying amount of intracytoplasmic lipid, and at unenhanced CT their density measurements are inversely related to the amount of lipid content.8 Based on this principle, adenomas can be separated from malignant masses using unenhanced CT density measurements.9,10 A threshold of 10 HU allowed adenoma to be diag- nosed with 71% sensitivity and 98% specificity on a meta-analysis, and is the stan- dard threshold used to diagnose a lipid-rich adenoma on CT (Fig. 2).11
The diagnosis of adenoma on CS-MRI also relies on the presence of intracytoplas- mic lipid, which leads to signal loss of an adenoma on out-of-phase compared with in- phase images.12,13 The signal loss can be quantified using signal intensity index with the diagnostic threshold at 16.5%.14 However, simple visual analysis is as effective and simpler to use, thus, is more commonly used in clinical practice. 15 AT CS-MRI, an adenoma is diagnosed when an adrenal mass becomes dark on out-of-phase compared with in-phase images, using the spleen as the reference (Fig. 3). With CS-MRI, adenomas are differentiated from metastasis with sensitivity and specificity of 81% to 100% and 94% to 100%, respectively.16,17
Approximately 20% to 30% of adrenal adenomas are lipid poor and do not contain sufficient amount of lipid to be diagnosed based on the CT density measurement or at CS-MRI. However, after enhancement with intravenous contrast, adenomas lose contrast rapidly, whereas the washout of metastases is more prolonged. 18,19 Based on this physiologic difference, adenomas can be separated from nonadenomas by calculating contrast washout percentage at a delayed phase, optimally 15 minutes af- ter contrast injection.18 The absolute percentage of enhancement washout (APW) is
calculated using the following formula, and a value of 60% or greater is diagnostic of an adenoma (Fig. 4):
APW = (enhanced HU) - (15 min delayed HU) (enhanced HU) - (unenhanced HU)
× 100%
In the absence of the initial unenhanced phase, a relative percentage washout (RPW) is calculated as follows, and a value of 40% or greater is diagnostic of an adenoma:
RPW = (enhanced HU) - (15 min delayed HU) (enhanced HU) × 100%
The accuracy of washout analysis has been confirmed on multiple studies.20-23 In one study of 166 adrenal masses, the combined adrenal protocol was 96% accurate in distinguishing adenoma from nonadenoma.22 Furthermore, the diagnostic accuracy is independent of lipid content.20,21
A
B
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B
C
Myelolipoma
Adrenal myelolipomas are benign tumors composed of mature fat and hematopoietic tissue. They are usually incidentally found asymptomatic masses, but large masses may rarely cause pain from spontaneous hemorrhage. With the widespread use of cross-sectional imaging, incidental detection of myelolipoma has increased.3 On CT and MRI, these lesions are easily recognized because they contain macroscopic fat, although the amount of fat and soft tissue is variable (Fig. 5). Pseudocapsules are common and calcifications are present in 24% of adrenal myelolipomas.24
Cyst and Pseudocyst
Adrenal cysts and pseudocysts are uncommon benign lesions usually found inciden- tally. They are mostly asymptomatic. Adrenal cysts are well-defined homogeneous round masses of near-water attenuation (0 HUs at CT) and a thin wall. On MRI, adrenal cysts also follow the signal of water (dark on T1-weighted images, bright on T2- weighted image) (Fig. 6). Adrenal cysts do not internally enhance using CT or MRI intravenous contrast. The wall may contain thin calcification, and the thin wall may enhance with intravenous contrast.25 Adrenal pseudocysts, which result from a previ- ous episode of hemorrhage, may appear more complex with higher internal density, thicker walls, internal septations, and calcifications.25
Adrenal Hemorrhage
Adrenal hemorrhage can occur in the setting of trauma, anticoagulation, blood dyscrasia, sepsis, hypotension, renal vein thrombosis, and severe stress such as sur- gery. Trauma accounts for 80% of adrenal hemorrhage, which is usually unilateral,
0
typically on the right. Adrenal hemorrhage can rarely result in adrenal insufficiency (Addison’s disease) if there is bilateral involvement. On CT, acute adrenal hematoma is round or oval with increased density of 50 to 90 HU on unenhanced CT (Fig. 7). The size and density of the mass decrease over time, and the mass usually resolves spon- taneously or calcifies, although some may liquefy and persist as pseudocysts. On MRI, the appearance of hematoma is variable depending on the age of hematoma, but most commonly is bright on T1-weighted images and dark on T2-weighted images.
Pheochromocytoma
Pheochromocytoma is an uncommon, catecholamine-secreting tumor arising from the adrenal medulla. Ten percent of pheochromocytomas are bilateral, 10% are mul- tiple, and 10% are associated with hereditary syndromes. Approximately 10% of pheochromocytomas are silent, although the number of incidentally discovered pheo- chromocytomas has been reported to be increasing.26,27 Pheochromocytomas have variable imaging appearances.28 On CT, small lesions are homogenous with soft tis- sue density (Fig. 8), but large masses are often heterogeneous and may contain areas of necrosis or hemorrhage. On MRI, pheochromocytomas have classically been described to be markedly hyperintense on T2-weighted images (Fig. 9); however,
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more recent series found that these tumors can be moderately hyperintense or even hypointese. 17,29 Pheochromocytomas usually enhance avidly after contrast injection. Approximately 10% of pheochromocytomas are malignant, but there are no specific radiologic features to diagnose malignancy other than invasion of local structures or distant metastases.
Adrenocortical Carcinoma
Adrenocortical carcinoma is a very rare, primary malignant tumor arising from the ad- renal cortex with prevalence of 1 to 2 patients per million population.30 It can be aggressive and typically presents late with a large mass. Approximately 50% of the carcinomas are hormonally active, most commonly producing cortisol, and may lead to Cushing syndrome. On CT and MRI, an adrenocortical carcinoma is a large (usually >6 cm) heterogeneously enhancing mass. It is frequently associated with cen- tral necrosis and hemorrhage, and calcifications are present in 30% (Fig. 10).31 Venous invasion into inferior vena cava is a common feature, often a diagnostic clue, and defining the superior extent of tumor thrombus is important for surgical planning to define the point for vascular control.
Metastasis
The adrenal glands are common sites of metastasis. At autopsy, adrenal metastases were found in 27% of patients with malignant epithelial tumors.32 Most patients with adrenal metastasis have an established extra-adrenal malignancy, and the common primary malignancies include carcinomas of the lung, breast, pancreas, and gastroin- testinal tract.33 When an adrenal mass is detected in oncologic patients, the main dilemma is whether the mass is a metastasis or an incidental benign adenoma. The imaging features of adrenal metastasis are often nonspecific at routine contrast- enhanced CT or MRI. Heterogeneous density, necrosis, and irregular margin can be present in metastasis, especially when they are large. However, small metastatic masses may be homogeneous with smooth margin, and appear benign.34 Thus, further characterization is often necessary using one of the imaging tools discussed above, especially if the adrenal gland is the only potential site of metastasis, as the diagnosis would likely alter the patient prognosis and treatment options. On unen- hanced CT, the metastatic adrenal masses usually measure greater than 10 HU. At
CT washout analysis, metastatic masses usually show delayed washout with APW less than 60% and RPW less than 40%.18,22 At MRI, most metastases are isointense to hypointense on T1-weighed sequence, usually hyperintense on T2-weighed sequence, and, most importantly, lack signal loss on opposed-phase at CS-MRI. At PET and PET-CT, most adrenal metastases are FDG-avid and show increased activity relative to the liver (Fig. 11). PET or PET-CT are found to differentiate benign from ma- lignant adrenal masses in cancer patients with sensitivity from 93% to 100%.35-38 Some benign lesions can show mildly increased uptake, and a recent meta-analysis reported specificity of PET to be at 91% in separating benign from malignant adrenal masses. 38
OPTIONS/PATHWAYS FOR SURGICAL INTERVENTION Hyperfunctioning Tumor
The search for a hyperfunctioning adrenal tumor is usually prompted by the clinical presentation of hormonal excess, which is confirmed by abnormal biochemical assay. The role of imaging is then primarily to detect the culprit mass, such as a cortisol- producing adenoma, an aldosteronoma, or a pheochromocytoma.
· Cortisol-producing adenomas, responsible for 20% of Cushing syndrome, are the most common cause of adrenocorticotropic hormone-independent Cushing syndrome. They are readily detected on CT, as they are typically larger than 2 cm. 17,39 These adenomas have similar CT appearance to that of nonfunctioning adenomas with abundant intracellular lipid causing a low-density adrenal mass. 8,39
· Aldosterone-producing adenomas, which cause 80% of Conn’s syndrome, are usually smaller than 2 cm with a significant portion less than 1 cm.40,41 Occasion- ally, adrenal vein sampling may still be necessary to localize and lateralize the site of hypersecretion when CT findings are equivocal. 42
. Once a pheochromocytoma is suspected clinically, the diagnosis is confirmed by elevated urine or plasma metanephrine levels. Ninety-eight percent of pheochro- mocytomas arise in the abdomen, mostly manifesting as adrenal masses, and they are readily localized on CT or MRI. Metaiodobenzylguanidine scintigraphy is highly accurate in diagnosing pheochromocytoma and is useful in those exceptional cases in which the mass is not identified on CT or MRI or in patients at risk of multiple pheochromocytoma and metastasis. 43,44
A
B
Imaging for Adrenal Gland Tumors
Incidental Adrenal Mass (≥1 cm) Detected on CT or MRI
Imaging features are diagnostic
Imaging features not diagnostic
>4 cm
Myelolipoma, ca++ = benign, no F/U
HU ≤10 or Į signal on CS-MRI = adenomaª
1-4 cm
No hx of cancer: consider resectionb
Hx of cancer: consider PET or biopsyb
Prior imaging
No prior imaging, No hx of cancer
No prior imaging, + hx of cancer
Stable ≥1 year
Lesion enlarging
Benign imaging features“: Presume benigna, consider 12 month F/U CT or MRI
Suspicious imaging featuresd
Consider PET or below
Benigna
Concerning for malignancy Consider biopsy or resectionb
Unenhanced CT or CS-MRI
HU ≤10 or Į signal on CS-MRI = adenomaª
HU >10 or no | signal on CS-MRI
Adrenal washout CT
No enhancement (≤10 HU) = cyst or hemorrhage
APW / RPW ≥60/40%
APW / RPW <60/40%
Benign, no F/U
Adenomaª
Biopsy if appropriateb or consider CS-MRI if not done
Incidental Adrenal Mass
Most incidentally detected adrenal masses are benign in patients without history of malignancy.3 In these patients, an exhaustive workup is not indicated for most small (<4 cm) asymptomatic masses. Imaging features, lesion size, lesion stability, and pa- tient history of malignancy are the primary factors that guide management of an inci- dental adrenal mass as they relate to risk of malignancy. An adrenal imaging flow chart from the white paper of the American College of Radiology Committee on Incidental Findings is presented in Fig. 12.45 The suggested algorithm is as follows:
· If an adrenal mass of any size has a specific diagnostic feature of a benign lesion, no additional imaging is warranted.
. For an adrenal mass smaller than 4 cm with nondiagnostic features, if the mass has been stable for at least a year, no follow-up is necessary, as it is likely benign. An enlarging mass should be biopsied or resected to exclude malignancy.
· For an adrenal mass smaller than 4 cm with nondiagnostic but benign-appearing features, if there is no prior imaging and no cancer history, follow-up unenhanced CT or CS-MRI in 12 months may be considered. If there are suspicious features, unenhanced CT or CS-MRI should be considered and, if needed, adrenal CT with washout analysis. If these studies do not confirm a benign diagnosis, biopsy would be prudent.
· In oncologic patients, if the adrenal mass does not have specific benign diag- nostic features and there is no prior imaging for comparison, unenhanced CT, CS-MRI, or PET should be performed, possibly proceeding to adrenal CT with washout analysis if needed. If none of these studies establish a benign diagnosis, then biopsy is appropriate.
. An adrenal mass larger than 4 cm is usually resected in patients without cancer history because of risk of adrenocortical carcinoma. In oncologic patients, PET or biopsy is recommended to exclude metastasis.
It is important to recognize that although recent advances in imaging have allowed noninvasive differentiation of adrenal adenomas from other adrenal lesions as described above, imaging cannot determine the functional status of an adrenal mass. Biochemical testing is required to determine if the adrenal mass is secreting excess hormones. Currently, most endocrinologists recommend screening biochem- ical assay for all incidental adrenal masses. However, because this approach would be costly, others recommend reserving full biochemical workup for those patients with clinical findings supportive of a hyperfunctioning tumor.45 Subclinical hyperfunction of an incidental adrenal mass is a new entity in which an incidental adrenal mass is detected and a biochemical assessment shows slightly elevated levels of hormone, but the patient is not symptomatic. The exact prevalence and management of patients with subclinical adrenal hyperfunction are still debated.
Fig. 12. Recommended algorithm for management of incidental adrenal masses as pro- posed by American College of Radiology. ª If patient has clinical sign or symptoms of adrenal hyperfunction, consider biochemical evaluation. b Consider biochemical testing to exclude pheochromocytoma. ” Benign imaging features = homogeneous, low density, smooth margins. d Suspicious imaging features = heterogeneous, necrosis, irregular margins. APW, absolute percentage washout; CS-MRI, chemical shift MRI; F/U, follow-up; HU, Houns- field unit; Hx, history; RPW, relative percentage washout; I, decrease. (From Berland LL, Silverman SG, Gore RM, et al. Managing incidental findings on abdominal CT: white paper of the American College of Radiology Incidental Findings Committee. J Am Coll Radiol 2010;7:764; with permission.)
SUMMARY
Adrenal glands can harbor a wide spectrum of pathology. Most incidental adrenal masses are benign in patients without malignancy, but in oncologic patients, adrenal glands are common sites of metastasis. Contemporary CT, MRI, and PET are excel- lent imaging tools in the detection and characterization of adrenal masses, and imag- ing findings alone can noninvasively diagnose most adrenal masses. The diagnosis of hyperfunctioning adrenal mass is made in conjunction with biochemical analysis. Appropriate utilization of imaging is important for optimal management of adrenal masses to separate benign inconsequential adrenal masses from those that require treatment.
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